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1. Biallelic variants in SLC4A10 encoding a sodium-dependent bicarbonate transporter lead to a neurodevelopmental disorder

Author

Maroofian, Reza, Zamani, Mina, Kaiyrzhanov, Rauan, Liebmann, Lutz, Karimiani, Ehsan Ghayoor, Vona, Barbara, Huebner, Antje K., Calame, Daniel G., Misra, Vinod K., Sadeghian, Saeid, Azizimalamiri, Reza, Mohammadi, Mohammad Hasan, Zeighami, Jawaher, Heydaran, Sogand, Toosi, Mehran Beiraghi, Akhondian, Javad, Babaei, Meisam, Hashemi, Narges, Schnur, Rhonda E., Suri, Mohnish, Setzke, Jonas, Wagner, Matias, Brunet, Theresa, Grochowski, Christopher M., Emrick, Lisa, Chung, Wendy K., Hellmich, Ute A., Schmidts, Miriam, Lupski, James R., Galehdari, Hamid, Severino, Mariasavina, Houlden, Henry, and Hübner, Christian A.

Published
2024
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4. SLC4A10 mutation causes a neurological disorder associated with impaired GABAergic transmission

Author

Fasham, James, primary, Huebner, Antje K, additional, Liebmann, Lutz, additional, Khalaf-Nazzal, Reham, additional, Maroofian, Reza, additional, Kryeziu, Nderim, additional, Wortmann, Saskia B, additional, Leslie, Joseph S, additional, Ubeyratna, Nishanka, additional, Mancini, Grazia M S, additional, van Slegtenhorst, Marjon, additional, Wilke, Martina, additional, Haack, Tobias B, additional, Shamseldin, Hanan, additional, Gleeson, Joseph G, additional, Almuhaizea, Mohamed, additional, Dweikat, Imad, additional, Abu-Libdeh, Bassam, additional, Daana, Muhannad, additional, Zaki, Maha S, additional, Wakeling, Matthew N, additional, McGavin, Lucy, additional, Turnpenny, Peter D, additional, Alkuraya, Fowzan S, additional, Houlden, Henry, additional, Schlattmann, Peter, additional, Kaila, Kai, additional, Crosby, Andrew H, additional, Baple, Emma L, additional, and Hübner, Christian A, additional

Published
2023
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5. MiT/TFE factors control ER‐phagy via transcriptional regulation of FAM134B

Author

Cinque, Laura, De Leonibus, Chiara, Iavazzo, Maria, Krahmer, Natalie, Intartaglia, Daniela, Salierno, Francesco Giuseppe, De Cegli, Rossella, Di Malta, Chiara, Svelto, Maria, Lanzara, Carmela, Maddaluno, Marianna, Wanderlingh, Luca Giorgio, Huebner, Antje K, Cesana, Marcella, Bonn, Florian, Polishchuk, Elena, Hübner, Christian A, Conte, Ivan, Dikic, Ivan, Mann, Matthias, Ballabio, Andrea, Sacco, Francesca, Grumati, Paolo, and Settembre, Carmine

Published
2020
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6. SLC4A10 mutation causes a neurological disorder associated with impaired GABAergic transmission

Author

Fasham, James, Huebner, Antje K., Liebmann, Lutz, Khalaf-Nazzal, Reham, Maroofian, Reza, Kryeziu, Nderim, Wortmann, Saskia B., Leslie, Joseph S., Ubeyratna, Nishanka, Mancini, Grazia M.S., van Slegtenhorst, Marjon, Wilke, Martina, Haack, Tobias B., Shamseldin, Hanan E., Gleeson, Joseph G., Almuhaizea, Mohamed, Dweikat, Imad, Abu-Libdeh, Bassam, Daana, Muhannad, Zaki, Maha S., Wakeling, Matthew N., McGavin, Lucy, Turnpenny, Peter D., Alkuraya, Fowzan S., Houlden, Henry, Schlattmann, Peter, Kaila, Kai, Crosby, Andrew H., Baple, Emma L., Hübner, Christian A., Fasham, James, Huebner, Antje K., Liebmann, Lutz, Khalaf-Nazzal, Reham, Maroofian, Reza, Kryeziu, Nderim, Wortmann, Saskia B., Leslie, Joseph S., Ubeyratna, Nishanka, Mancini, Grazia M.S., van Slegtenhorst, Marjon, Wilke, Martina, Haack, Tobias B., Shamseldin, Hanan E., Gleeson, Joseph G., Almuhaizea, Mohamed, Dweikat, Imad, Abu-Libdeh, Bassam, Daana, Muhannad, Zaki, Maha S., Wakeling, Matthew N., McGavin, Lucy, Turnpenny, Peter D., Alkuraya, Fowzan S., Houlden, Henry, Schlattmann, Peter, Kaila, Kai, Crosby, Andrew H., Baple, Emma L., and Hübner, Christian A.

Abstract

SLC4A10 is a plasma-membrane bound transporter that utilizes the Na+ gradient to drive cellular HCO3- uptake, thus mediating acid extrusion. In the mammalian brain, SLC4A10 is expressed in principal neurons and interneurons, as well as in epithelial cells of the choroid plexus, the organ regulating the production of CSF. Using next generation sequencing on samples from five unrelated families encompassing nine affected individuals, we show that biallelic SLC4A10 loss-of-function variants cause a clinically recognizable neurodevelopmental disorder in humans. The cardinal clinical features of the condition include hypotonia in infancy, delayed psychomotor development across all domains and intellectual impairment. Affected individuals commonly display traits associated with autistic spectrum disorder including anxiety, hyperactivity and stereotyped movements. In two cases isolated episodes of seizures were reported in the first few years of life, and a further affected child displayed bitemporal epileptogenic discharges on EEG without overt clinical seizures. While occipitofrontal circumference was reported to be normal at birth, progressive postnatal microcephaly evolved in 7 out of 10 affected individuals. Neuroradiological features included a relative preservation of brain volume compared to occipitofrontal circumference, characteristic narrow sometimes 'slit-like' lateral ventricles and corpus callosum abnormalities. Slc4a10 -/- mice, deficient for SLC4A10, also display small lateral brain ventricles and mild behavioural abnormalities including delayed habituation and alterations in the two-object novel object recognition task. Collapsed brain ventricles in both Slc4a10-/- mice and affected individuals suggest an important role of SLC4A10 in the production of the CSF. However, it is notable that despite diverse roles of the CSF in the developing and adult brain, the cortex of Slc4a10-/- mice appears grossly intact. Co-staining with synaptic markers revealed tha

Published
2023

7. Disruption of vascular [Ca.sup.2+]-activated chloride currents lowers blood pressure

Author

Heinze, Christoph, Seniuk, Anika, Sokolov, Maxim V., Huebner, Antje K., Klementowicz, Agnieszka E., Szijarto, Istvan A., Schleifenbaum, Johanna, Vitzthum, Helga, Gollasch, Maik, Ehmke, Heimo, Schroeder, Bjorn C., and Hubner, Christian A.

Subjects
Membrane proteins -- Physiological aspects -- Research, Chloride channels -- Physiological aspects -- Research, Vascular smooth muscle -- Physiological aspects -- Research, Hypertension -- Care and treatment -- Research, Health care industry
Abstract

High blood pressure is the leading risk factor for death worldwide. One of the hallmarks is a rise of peripheral vascular resistance, which largely depends on arteriole tone. [Ca.sup.2+]-activated chloride currents (CaCCs) in vascular smooth muscle cells (VSMCs) are candidates for increasing vascular contractility. We analyzed the vascular tree and identified substantial CaCCs in VSMCs of the aorta and carotid arteries. CaCCs were small or absent in VSMCs of medium-sized vessels such as mesenteric arteries and larger retinal arterioles. In small vessels of the retina, brain, and skeletal muscle, where contractile intermediate cells or pericytes gradually replace VSMCs, CaCCs were particularly large. Targeted disruption of the calcium-activated chloride channel TMEM16A, also known as ANO1, in VSMCs, intermediate cells, and pericytes eliminated CaCCs in all vessels studied. Mice lacking vascular TMEM16A had lower systemic blood pressure and a decreased hypertensive response following vasoconstrictor treatment. There was no difference in contractility of medium-sized mesenteric arteries; however, responsiveness of the aorta and small retinal arterioles to the vasoconstrictioninducing drug U46619 was reduced. TMEM16A also was required for peripheral blood vessel contractility, as the response to U46619 was attenuated in isolated perfused hind limbs from mutant mice. Out data suggest that TMEM16A plays a general role in arteriolar and capillary blood flow and is a promising target for the treatment of hypertension., Introduction With more than 25% of the adult population being affected, hypertension is an important public health challenge worldwide (1). It is a major risk factor for cardiovascular disease, myocardial [...]

Published
2014
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8. Regulation of endoplasmic reticulum turnover by selective autophagy

Author

Khaminets, Aliaksandr, Heinrich, Theresa, Mari, Muriel, Grumati, Paolo, Huebner, Antje K., Akutsu, Masato, Liebmann, Lutz, Stolz, Alexandra, Nietzsche, Sandor, Koch, Nicole, Mauthe, Mario, Katona, Istvan, Qualmann, Britta, Weis, Joachim, Reggiori, Fulvio, Kurth, Ingo, Hübner, Christian A., and Dikic, Ivan

Published
2015
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12. Impaired gastric acidification negatively affects calcium homeostasis and bone mass

Author

Schinke, Thorsten, Schilling, Arndt F., Baranowsky, Anke, Seitz, Sebastian, Marshall, Robert P., Linn, Tilman, Blaeker, Michael, Huebner, Antje K., Schulz, Ansgar, Simon, Ronald, Gebauer, Matthias, Priemel, Matthias, Kornak, Uwe, Perkovic, Sandra, Barvencik, Florian, Beil, F. Timo, Del Fattore, Andrea, Frattini, Annalisa, Streichert, Thomas, Pueschel, Klaus, Villa, Anna, Debatin, Klaus-Michael, Rueger, Johannes M., Teti, Anna, Zustin, Jozef, Sauter, Guido, and Amling, Michael

Subjects
Peptide hormones -- Research, Osteoporosis -- Diagnosis, Osteoporosis -- Genetic aspects, Osteoporosis -- Care and treatment, Gastric acid -- Health aspects, Bones -- Density, Bones -- Health aspects
Abstract

Activation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. Here we show that osteoclast dysfunction alone does not generally affect calcium homeostasis. Indeed, mice deficient in Src, encoding a tyrosine kinase critical for osteoclast activity, show signs of osteopetrosis, but without hypocalcemia or defects in bone mineralization. Mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells, have the expected defects in gastric acidification but also secondary hyperparathyroidism and osteoporosis and modest hypocalcemia. These results suggest that alterations in calcium homeostasis can be driven by defects in gastric acidification, especially given that calcium gluconate supplementation fully rescues the phenotype of the Cckbr-mutant mice. Finally, mice deficient in Tcirg1, encoding a subunit of the vacuolar proton pump specifically expressed in both osteoclasts and parietal cells, show hypocalcemia and osteopetrorickets. Although neither Src- nor Cckbr-deficient mice have this latter phenotype, the combined deficiency of both genes results in osteopetrorickets. Thus, we find that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification., Bone is constantly remodeled through the balanced activities of osteoblasts and osteoclasts. Whereas genetic defects of bone-forming osteoblasts typically result in delayed bone development and osteoporosis, mutational inactivation of bone-resorbing [...]

Published
2009

13. MiT/TFEfactors controlER-phagy via transcriptional regulation ofFAM134B

Author

Cinque, Laura, De Leonibus, Chiara, Iavazzo, Maria, Krahmer, Natalie, Intartaglia, Daniela, Salierno, Francesco Giuseppe, De Cegli, Rossella, Di Malta, Chiara, Svelto, Maria, Lanzara, Carmela, Maddaluno, Marianna, Wanderlingh, Luca Giorgio, Huebner, Antje K., Cesana, Marcella, Bonn, Florian, Polishchuk, Elena, Huebner, Christian A., Conte, Ivan, Dikic, Ivan, Mann, Matthias, Ballabio, Andrea, Sacco, Francesca, Grumati, Paolo, Settembre, Carmine, Cinque, Laura, De Leonibus, Chiara, Iavazzo, Maria, Krahmer, Natalie, Intartaglia, Daniela, Salierno, Francesco Giuseppe, De Cegli, Rossella, Di Malta, Chiara, Svelto, Maria, Lanzara, Carmela, Maddaluno, Marianna, Wanderlingh, Luca Giorgio, Huebner, Antje K., Cesana, Marcella, Bonn, Florian, Polishchuk, Elena, Huebner, Christian A., Conte, Ivan, Dikic, Ivan, Mann, Matthias, Ballabio, Andrea, Sacco, Francesca, Grumati, Paolo, and Settembre, Carmine

Abstract

Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is emerging as a critical regulator of cell homeostasis and function. The recent identification ofER-phagy receptors has shed light on the molecular mechanisms underlining this process. However, the signaling pathways regulatingER-phagy in response to cellular needs are still largely unknown. We found that the nutrient responsive transcription factorsTFEBandTFE3-master regulators of lysosomal biogenesis and autophagy-controlER-phagy by inducing the expression of theER-phagy receptorFAM134B. TheTFEB/TFE3-FAM134B axis promotesER-phagy activation upon prolonged starvation. In addition, this pathway is activated in chondrocytes byFGFsignaling, a critical regulator of skeletal growth.FGFsignaling inducesJNK-dependent proteasomal degradation of the insulin receptor substrate 1 (IRS1), which in turn inhibits thePI3K-PKB/Akt-mTORC1 pathway and promotesTFEB/TFE3 nuclear translocation and enhancesFAM134B transcription. Notably,FAM134B is required for protein secretion in chondrocytes, and cartilage growth and bone mineralization in medaka fish. This study identifies a new signaling pathway that allowsER-phagy to respond to both metabolic and developmental cues.

Published
2020

14. Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia

Author

Husain, Ralf A., primary, Grimmel, Mona, additional, Wagner, Matias, additional, Hennings, J. Christopher, additional, Marx, Christian, additional, Feichtinger, René G., additional, Saadi, Abdelkrim, additional, Rostásy, Kevin, additional, Radelfahr, Florentine, additional, Bevot, Andrea, additional, Döbler-Neumann, Marion, additional, Hartmann, Hans, additional, Colleaux, Laurence, additional, Cordts, Isabell, additional, Kobeleva, Xenia, additional, Darvish, Hossein, additional, Bakhtiari, Somayeh, additional, Kruer, Michael C., additional, Besse, Arnaud, additional, Ng, Andy Cheuk-Him, additional, Chiang, Diana, additional, Bolduc, Francois, additional, Tafakhori, Abbas, additional, Mane, Shrikant, additional, Ghasemi Firouzabadi, Saghar, additional, Huebner, Antje K., additional, Buchert, Rebecca, additional, Beck-Woedl, Stefanie, additional, Müller, Amelie J., additional, Laugwitz, Lucia, additional, Nägele, Thomas, additional, Wang, Zhao-Qi, additional, Strom, Tim M., additional, Sturm, Marc, additional, Meitinger, Thomas, additional, Klockgether, Thomas, additional, Riess, Olaf, additional, Klopstock, Thomas, additional, Brandl, Ulrich, additional, Hübner, Christian A., additional, Deschauer, Marcus, additional, Mayr, Johannes A., additional, Bonnen, Penelope E., additional, Krägeloh-Mann, Ingeborg, additional, Wortmann, Saskia B., additional, and Haack, Tobias B., additional

Published
2020
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15. MiT/ TFE factors control ER ‐phagy via transcriptional regulation of FAM 134B

Author

Cinque, Laura, primary, Leonibus, Chiara, additional, Iavazzo, Maria, additional, Krahmer, Natalie, additional, Intartaglia, Daniela, additional, Salierno, Francesco Giuseppe, additional, De Cegli, Rossella, additional, Di Malta, Chiara, additional, Svelto, Maria, additional, Lanzara, Carmela, additional, Maddaluno, Marianna, additional, Wanderlingh, Luca Giorgio, additional, Huebner, Antje K, additional, Cesana, Marcella, additional, Bonn, Florian, additional, Polishchuk, Elena, additional, Hübner, Christian A, additional, Conte, Ivan, additional, Dikic, Ivan, additional, Mann, Matthias, additional, Ballabio, Andrea, additional, Sacco, Francesca, additional, Grumati, Paolo, additional, and Settembre, Carmine, additional

Published
2020
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16. Intercalated cell depletion and vacuolar H+-ATPase mistargeting in an AE1 R607H knockin model

Author

Mumtaz, Rizwan, Trepiccione, Francesco, Hennings, J Christopher, Huebner, Antje K, Serbin, Bettina, Picard, Nicolas, Ullah, A K M Shahid, Păunescu, Teodor G, Capen, Diane E, Lashhab, Rawad M, Mouro-Chanteloup, Isabelle, Alper, Seth L, Wagner, Carsten A, Cordat, Emmanuelle, Brown, Dennis, Eladari, Dominique, Hübner, Christian A, Mumtaz, Rizwan, Trepiccione, Francesco, Hennings, J Christopher, Huebner, Antje K, Serbin, Bettina, Picard, Nicolas, Ullah, A K M Shahid, Păunescu, Teodor G, Capen, Diane E, Lashhab, Rawad M, Mouro-Chanteloup, Isabelle, Alper, Seth L, Wagner, Carsten A, Cordat, Emmanuelle, Brown, Dennis, Eladari, Dominique, and Hübner, Christian A

Abstract

Distal nephron acid secretion is mediated by highly specialized type A intercalated cells (A-ICs), which contain vacuolar H(+)-ATPase (V-type ATPase)-rich vesicles that fuse with the apical plasma membrane on demand. Intracellular bicarbonate generated by luminal H(+) secretion is removed by the basolateral anion-exchanger AE1. Chronically reduced renal acid excretion in distal renal tubular acidosis (dRTA) may lead to nephrocalcinosis and renal failure. Studies in MDCK monolayers led to the proposal of a dominant-negative trafficking mechanism to explain AE1-associated dominant dRTA. To test this hypothesis in vivo, we generated an Ae1 R607H knockin mouse, which corresponds to the most common dominant dRTA mutation in human AE1, R589H. Compared with wild-type mice, heterozygous and homozygous R607H knockin mice displayed incomplete dRTA characterized by compensatory upregulation of the Na(+)/HCO3(-) cotransporter NBCn1. Red blood cell Ae1-mediated anion-exchange activity and surface polypeptide expression did not change. Mutant mice expressed far less Ae1 in A-ICs, but basolateral targeting of the mutant protein was preserved. Notably, mutant mice also exhibited reduced expression of V-type ATPase and compromised targeting of this proton pump to the plasma membrane upon acid challenge. Accumulation of p62- and ubiquitin-positive material in A-ICs of knockin mice suggested a defect in the degradative pathway, which may explain the observed loss of A-ICs. R607H knockin did not affect type B intercalated cells. We propose that reduced basolateral anion-exchange activity in A-ICs inhibits trafficking and regulation of V-type ATPase, compromising luminal H(+) secretion and possibly lysosomal acidification.

Published
2017

18. Intercalated Cell Depletion and Vacuolar H+-ATPase Mistargeting in an Ae1 R607H Knockin Model

Author

Mumtaz, Rizwan, primary, Trepiccione, Francesco, additional, Hennings, J. Christopher, additional, Huebner, Antje K., additional, Serbin, Bettina, additional, Picard, Nicolas, additional, Ullah, A. K. M. Shahid, additional, Păunescu, Teodor G., additional, Capen, Diane E., additional, Lashhab, Rawad M., additional, Mouro-Chanteloup, Isabelle, additional, Alper, Seth L., additional, Wagner, Carsten A., additional, Cordat, Emmanuelle, additional, Brown, Dennis, additional, Eladari, Dominique, additional, and Hübner, Christian A., additional

Published
2016
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19. The ClC-K2 Chloride Channel Is Critical for Salt Handling in the Distal Nephron

Author

Hennings, J. Christopher, primary, Andrini, Olga, additional, Picard, Nicolas, additional, Paulais, Marc, additional, Huebner, Antje K., additional, Cayuqueo, Irma Karen Lopez, additional, Bignon, Yohan, additional, Keck, Mathilde, additional, Cornière, Nicolas, additional, Böhm, David, additional, Jentsch, Thomas J., additional, Chambrey, Régine, additional, Teulon, Jacques, additional, Hübner, Christian A., additional, and Eladari, Dominique, additional

Published
2016
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20. Regulation of endoplasmic reticulum turnover by selective autophagy

Author

CMM Groep de Rooij, Khaminets, Aliaksandr, Heinrich, Theresa, Mari, Muriel, Grumati, Paolo, Huebner, Antje K, Akutsu, Masato, Liebmann, Lutz, Stolz, Alexandra, Nietzsche, Sandor, Koch, Nicole, Mauthe, Mario, Katona, Istvan, Qualmann, Britta, Weis, Joachim, Reggiori, Fulvio, Kurth, Ingo, Hübner, Christian A, Dikic, Ivan, CMM Groep de Rooij, Khaminets, Aliaksandr, Heinrich, Theresa, Mari, Muriel, Grumati, Paolo, Huebner, Antje K, Akutsu, Masato, Liebmann, Lutz, Stolz, Alexandra, Nietzsche, Sandor, Koch, Nicole, Mauthe, Mario, Katona, Istvan, Qualmann, Britta, Weis, Joachim, Reggiori, Fulvio, Kurth, Ingo, Hübner, Christian A, and Dikic, Ivan

Published
2015

21. Lack of the sodium-driven chloride bicarbonate exchanger NCBE impairs visual function in the mouse retina

Author

Neuhauss, Stephan CF., Hilgen, Gerrit, Huebner, Antje K., Tanimoto, Naoyuki, Sothilingam, Vithiyanjali, Seide, Christina, Garrido, Marina Garcia, Schmidt, Karl-Friedrich, Seeliger, Mathias W., Löwel, Siegrid, Weiler, Reto, Hübner, Christian A., and Dedek, Karin

Subjects
Central Nervous System, Anatomy and Physiology, Mouse, Visual System, Visual Acuity, Neural Homeostasis, D300, Retinal Pigment Epithelium, Biochemistry, Ion Channels, chemistry.chemical_compound, Mice, Molecular Cell Biology, Membrane Receptor Signaling, Chloride-Bicarbonate Antiporters, Axon, Mice, Knockout, Multidisciplinary, Microscopy, Confocal, Symporters, GABAA receptor, C100, Neurotransmitter Receptor Signaling, Depolarization, Neurochemistry, Anatomy, Neurotransmitters, Animal Models, Immunohistochemistry, Sensory Systems, C900, Cell biology, Electrophysiology, medicine.anatomical_structure, Medicine, Neurochemicals, Intracellular, Research Article, Signal Transduction, Retinal Bipolar Cells, Intracellular pH, Bicarbonate, Science, Neurophysiology, Biology, Retina, Contrast Sensitivity, Model Organisms, medicine, Electroretinography, Animals, Sodium-Bicarbonate Symporters, Ophthalmology, Amacrine Cells, chemistry, Cellular Neuroscience, Ganglia, sense organs, Photic Stimulation, Neuroscience
Abstract

Regulation of ion and pH homeostasis is essential for normal neuronal function. The sodium-driven chloride bicarbonate exchanger NCBE (Slc4a10), a member of the SLC4 family of bicarbonate transporters, uses the transmembrane gradient of sodium to drive cellular net uptake of bicarbonate and to extrude chloride, thereby modulating both intracellular pH (pH(i)) and chloride concentration ([Cl(-)](i)) in neurons. Here we show that NCBE is strongly expressed in the retina. As GABA(A) receptors conduct both chloride and bicarbonate, we hypothesized that NCBE may be relevant for GABAergic transmission in the retina. Importantly, we found a differential expression of NCBE in bipolar cells: whereas NCBE was expressed on ON and OFF bipolar cell axon terminals, it only localized to dendrites of OFF bipolar cells. On these compartments, NCBE colocalized with the main neuronal chloride extruder KCC2, which renders GABA hyperpolarizing. NCBE was also expressed in starburst amacrine cells, but was absent from neurons known to depolarize in response to GABA, like horizontal cells. Mice lacking NCBE showed decreased visual acuity and contrast sensitivity in behavioral experiments and smaller b-wave amplitudes and longer latencies in electroretinograms. Ganglion cells from NCBE-deficient mice also showed altered temporal response properties. In summary, our data suggest that NCBE may serve to maintain intracellular chloride and bicarbonate concentration in retinal neurons. Consequently, lack of NCBE in the retina may result in changes in pH(i) regulation and chloride-dependent inhibition, leading to altered signal transmission and impaired visual function.

Published
2012

22. In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11

Author

Varga, Rita-Eva, primary, Khundadze, Mukhran, additional, Damme, Markus, additional, Nietzsche, Sandor, additional, Hoffmann, Birgit, additional, Stauber, Tobias, additional, Koch, Nicole, additional, Hennings, J. Christopher, additional, Franzka, Patricia, additional, Huebner, Antje K., additional, Kessels, Michael M., additional, Biskup, Christoph, additional, Jentsch, Thomas J., additional, Qualmann, Britta, additional, Braulke, Thomas, additional, Kurth, Ingo, additional, Beetz, Christian, additional, and Hübner, Christian A., additional

Published
2015
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23. Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts

Author

Keller, Johannes, primary, Catala-Lehnen, Philip, additional, Huebner, Antje K., additional, Jeschke, Anke, additional, Heckt, Timo, additional, Lueth, Anja, additional, Krause, Matthias, additional, Koehne, Till, additional, Albers, Joachim, additional, Schulze, Jochen, additional, Schilling, Sarah, additional, Haberland, Michael, additional, Denninger, Hannah, additional, Neven, Mona, additional, Hermans-Borgmeyer, Irm, additional, Streichert, Thomas, additional, Breer, Stefan, additional, Barvencik, Florian, additional, Levkau, Bodo, additional, Rathkolb, Birgit, additional, Wolf, Eckhard, additional, Calzada-Wack, Julia, additional, Neff, Frauke, additional, Gailus-Durner, Valerie, additional, Fuchs, Helmut, additional, de Angelis, Martin Hrab[ebreve], additional, Klutmann, Susanne, additional, Tsourdi, Elena, additional, Hofbauer, Lorenz C., additional, Kleuser, Burkhard, additional, Chun, Jerold, additional, Schinke, Thorsten, additional, and Amling, Michael, additional

Published
2014
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24. Mutations in GMPPA Cause a Glycosylation Disorder Characterized by Intellectual Disability and Autonomic Dysfunction

Author

Koehler, Katrin, Malik, Meera, Mahmood, Saqib, Giesselmann, Sebastian, Beetz, Christian, Hennings, J. Christopher, Huebner, Antje K., Grahn, Ammi, Reunert, Janine, Nuernberg, Gudrun, Thiele, Holger, Altmueller, Janine, Nuernberg, Peter, Mumtaz, Rizwan, Babovic-Vuksanovic, Dusica, Basel-Vanagaite, Lina, Borck, Guntram, Braemswig, Jurgen, Muehlenberg, Reinhard, Sarda, Pierre, Sikiric, Alma, Anyane-Yeboa, Kwame, Zeharia, Avraham, Ahmad, Arsalan, Coubes, Christine, Wada, Yoshinao, Marquardt, Thorsten, Vanderschaeghe, Dieter, Van Schaftingen, Emile, Kurth, Ingo, Huebner, Angela, Huebner, Christian A., Koehler, Katrin, Malik, Meera, Mahmood, Saqib, Giesselmann, Sebastian, Beetz, Christian, Hennings, J. Christopher, Huebner, Antje K., Grahn, Ammi, Reunert, Janine, Nuernberg, Gudrun, Thiele, Holger, Altmueller, Janine, Nuernberg, Peter, Mumtaz, Rizwan, Babovic-Vuksanovic, Dusica, Basel-Vanagaite, Lina, Borck, Guntram, Braemswig, Jurgen, Muehlenberg, Reinhard, Sarda, Pierre, Sikiric, Alma, Anyane-Yeboa, Kwame, Zeharia, Avraham, Ahmad, Arsalan, Coubes, Christine, Wada, Yoshinao, Marquardt, Thorsten, Vanderschaeghe, Dieter, Van Schaftingen, Emile, Kurth, Ingo, Huebner, Angela, and Huebner, Christian A.

Abstract

In guanosine diphosphate (GDP)-mannose pyrophosphorylase A (GMPPA), we identified a homozygous nonsense mutation that segregated with achalasia and alacrima, delayed developmental milestones, and gait abnormalities in a consanguineous Pakistani pedigree. Mutations in GMPPA were subsequently found in ten additional individuals from eight independent families affected by the combination of achalasia, alacrima, and neurological deficits. This autosomal-recessive disorder shows many similarities with triple A syndrome, which is characterized by achalasia, alacrima, and variable neurological deficits in combination with adrenal insufficiency. GMPPA is a largely uncharacterized homolog of GMPPB. GMPPB catalyzes the formation of GDP-mannose, which is an essential precursor of glycan moieties of glycoproteins and glycolipids and is associated with congenital and limb-girdle muscular dystrophies with hypoglycosylation of a-dystroglycan. Surprisingly, GDP-mannose pyrophosphorylase activity was unchanged and GDP-mannose levels were strongly increased in lymphoblasts of individuals with GMPPA mutations. This suggests that GMPPA might serve as a GMPPB regulatory subunit mediating feedback inhibition of GMPPB instead of displaying catalytic enzyme activity itself. Thus, a triple-A-like syndrome can be added to the growing list of congenital disorders of glycosylation, in which dysregulation rather than mere enzyme deficiency is the basal pathophysiological mechanism.

Published
2013

25. A Hereditary Spastic Paraplegia Mouse Model Supports a Role of ZFYVE26/SPASTIZIN for the Endolysosomal System

Author

Khundadze, Mukhran, primary, Kollmann, Katrin, additional, Koch, Nicole, additional, Biskup, Christoph, additional, Nietzsche, Sandor, additional, Zimmer, Geraldine, additional, Hennings, J. Christopher, additional, Huebner, Antje K., additional, Symmank, Judit, additional, Jahic, Amir, additional, Ilina, Elena I., additional, Karle, Kathrin, additional, Schöls, Ludger, additional, Kessels, Michael, additional, Braulke, Thomas, additional, Qualmann, Britta, additional, Kurth, Ingo, additional, Beetz, Christian, additional, and Hübner, Christian A., additional

Published
2013
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26. Mutations in GMPPA Cause a Glycosylation Disorder Characterized by Intellectual Disability and Autonomic Dysfunction

Author

Koehler, Katrin, primary, Malik, Meera, additional, Mahmood, Saqib, additional, Gießelmann, Sebastian, additional, Beetz, Christian, additional, Hennings, J. Christopher, additional, Huebner, Antje K., additional, Grahn, Ammi, additional, Reunert, Janine, additional, Nürnberg, Gudrun, additional, Thiele, Holger, additional, Altmüller, Janine, additional, Nürnberg, Peter, additional, Mumtaz, Rizwan, additional, Babovic-Vuksanovic, Dusica, additional, Basel-Vanagaite, Lina, additional, Borck, Guntram, additional, Brämswig, Jürgen, additional, Mühlenberg, Reinhard, additional, Sarda, Pierre, additional, Sikiric, Alma, additional, Anyane-Yeboa, Kwame, additional, Zeharia, Avraham, additional, Ahmad, Arsalan, additional, Coubes, Christine, additional, Wada, Yoshinao, additional, Marquardt, Thorsten, additional, Vanderschaeghe, Dieter, additional, Van Schaftingen, Emile, additional, Kurth, Ingo, additional, Huebner, Angela, additional, and Hübner, Christian A., additional

Published
2013
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27. Lack of the Sodium-Driven Chloride Bicarbonate Exchanger NCBE Impairs Visual Function in the Mouse Retina

Author

Hilgen, Gerrit, primary, Huebner, Antje K., additional, Tanimoto, Naoyuki, additional, Sothilingam, Vithiyanjali, additional, Seide, Christina, additional, Garrido, Marina Garcia, additional, Schmidt, Karl-Friedrich, additional, Seeliger, Mathias W., additional, Löwel, Siegrid, additional, Weiler, Reto, additional, Hübner, Christian A., additional, and Dedek, Karin, additional

Published
2012
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28. Nonsense Mutations in SMPX, Encoding a Protein Responsive to Physical Force, Result in X-Chromosomal Hearing Loss

Author

Huebner, Antje K., primary, Gandia, Marta, additional, Frommolt, Peter, additional, Maak, Anika, additional, Wicklein, Eva M., additional, Thiele, Holger, additional, Altmüller, Janine, additional, Wagner, Florian, additional, Viñuela, Antonio, additional, Aguirre, Luis A., additional, Moreno, Felipe, additional, Maier, Hannes, additional, Rau, Isabella, additional, Gießelmann, Sebastian, additional, Nürnberg, Gudrun, additional, Gal, Andreas, additional, Nürnberg, Peter, additional, Hübner, Christian A., additional, del Castillo, Ignacio, additional, and Kurth, Ingo, additional

Published
2011
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29. Mutations in FAM134B, encoding a newly identified Golgi protein, cause severe sensory and autonomic neuropathy

Author

Kurth, Ingo, primary, Pamminger, Torsten, additional, Hennings, J Christopher, additional, Soehendra, Désirée, additional, Huebner, Antje K, additional, Rotthier, Annelies, additional, Baets, Jonathan, additional, Senderek, Jan, additional, Topaloglu, Haluk, additional, Farrell, Sandra A, additional, Nürnberg, Gudrun, additional, Nürnberg, Peter, additional, De Jonghe, Peter, additional, Gal, Andreas, additional, Kaether, Christoph, additional, Timmerman, Vincent, additional, and Hübner, Christian A, additional

Published
2009
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32. Biallelic variants in SLC4A10encoding the sodium-dependent chloride-bicarbonate exchanger NCBE lead to a neurodevelopmental disorder.

Author

Maroofian, Reza, Zamani, Mina, Kaiyrzhanov, Rauan, Liebmann, Lutz, Ghayoor Karimiani, Ehsan, Vona, Barbara, Huebner, Antje K., Calame, Daniel G., Misra, Vinod K., Sadeghian, Saeid, Azizimalamiri, Reza, Mohammadi, Mohammad Hasan, Zeighami, Jawaher, Heydaran, Sogand, Beiraghi Toosi, Mehran, Akhondian, Javad, Babaei, Meisam, Hashemi, Narges, Schnur, Rhonda E., Suri, Mohnish, Setzke, Jonas, Wagner, Matias, Brunet, Theresa, Grochowski, Christopher M., Emrick, Lisa, Chung, Wendy K., Hellmich, Ute A., Schmidts, Miriam, Lupski, James R., Galehdari, Hamid, Severino, Mariasavina, Houlden, Henry, and Hübner, Christian A.

Abstract

SLC4A10encodes a plasma membrane-bound transporter, which mediates Na+-dependent HCO3−import thus mediating net acid extrusion. Slc4a10knockout (KO) mice show collapsed brain ventricles, an increased seizure threshold, mild behavioral abnormalities, impaired vision, and deafness.

Published
2023
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33. Disruption of vascular Ca2+-activated chloride currents lowers blood pressure.

Author

Heinze, Christoph, Seniuk, Anika, Sokolov, Maxim V., Huebner, Antje K., Klementowicz, Agnieszka E., Szijártó, István A., Schleifenbaum, Johanna, Vitzthum, Helga, Gollasch, Maik, Ehmke, Heimo, Schroeder, Bjorn C., and Hubner, Christian A.

Subjects
*CHLORIDE channels, *CALCIUM, *MUSCLE cells, *VASCULAR smooth muscle physiology, *BLOOD pressure, *VASOCONSTRICTION, *LABORATORY mice
Abstract

High blood pressure is the leading risk factor for death worldwide. One of the hallmarks is a rise of peripheral vascular resistance, which largely depends on arteriole tone. Ca2+-activated chloride currents (CaCCs) in vascular smooth muscle cells (VSMCs) are candidates for increasing vascular contractility. We analyzed the vascular tree and identified substantial CaCCs in VSMCs of the aorta and carotid arteries. CaCCs were small or absent in VSMCs of medium-sized vessels such as mesenteric arteries and larger retinal arterioles. In small vessels of the retina, brain, and skeletal muscle, where contractile intermediate cells or pericytes gradually replace VSMCs, CaCCs were particularly large. Targeted disruption of the calcium-activated chloride channel TMEM16A, also known as ANO1, in VSMCs, intermediate cells, and pericytes eliminated CaCCs in all vessels studied. Mice lacking vascular TMEM16A had lower systemic blood pressure and a decreased hypertensive response following vasoconstrictor treatment. There was no difference in contractility of medium-sized mesenteric arteries; however, responsiveness of the aorta and small retinal arterioles to the vasoconstriction-inducing drug U46619 was reduced. TMEM16A also was required for peripheral blood vessel contractility, as the response to U46619 was attenuated in isolated perfused hind limbs from mutant mice. Out data suggest that TMEM16A plays a general role in arteriolar and capillary blood flow and is a promising target for the treatment of hypertension. [ABSTRACT FROM AUTHOR]

Published
2014
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34. MiT/ <scp>TFE</scp> factors control <scp>ER</scp> ‐phagy via transcriptional regulation of <scp>FAM</scp> 134B

Author

Marianna Maddaluno, Carmela Lanzara, Paolo Grumati, Ivan Conte, Christian A. Hübner, Chiara Di Malta, Maria Iavazzo, Antje K. Huebner, Daniela Intartaglia, Carmine Settembre, Francesco Giuseppe Salierno, Chiara De Leonibus, Florian Bonn, Maria Svelto, Rossella De Cegli, Matthias Mann, Ivan Dikic, Luca Giorgio Wanderlingh, Laura Cinque, Francesca Sacco, Elena Polishchuk, Andrea Ballabio, Marcella Cesana, Natalie Krahmer, Cinque, Laura, De Leonibus, Chiara, Iavazzo, Maria, Krahmer, Natalie, Intartaglia, Daniela, Salierno, Francesco Giuseppe, De Cegli, Rossella, Di Malta, Chiara, Svelto, Maria, Lanzara, Carmela, Maddaluno, Marianna, Wanderlingh, Luca Giorgio, Huebner, Antje K, Cesana, Marcella, Bonn, Florian, Polishchuk, Elena, Hübner, Christian A, Conte, Ivan, Dikic, Ivan, Mann, Matthia, Ballabio, Andrea, Sacco, Francesca, Grumati, Paolo, and Settembre, Carmine

Subjects
MECHANISM, ER-phagy, IRS1, ENDOPLASMIC-RETICULUM, Regulator, Biology, Fibroblast growth factor, Chromatin, Epigenetics, Genomics & Functional Genomics, Article, General Biochemistry, Genetics and Molecular Biology, FGF signaling, 03 medical and health sciences, 0302 clinical medicine, Transcriptional regulation, FGF, Fam134B, NETWORK, ER‐phagy, FGFsignaling, Musculoskeletal System, Molecular Biology, Transcription factor, PI3K signaling, 030304 developmental biology, TFEB, 0303 health sciences, RECEPTOR, Settore BIO/18, General Immunology and Microbiology, IRS1/PI3K signaling, General Neuroscience, Endoplasmic reticulum, Autophagy, Er-phagy, Fam134b, Fgfsignaling, Irs1, Pi3k Signaling, Tfeb, Articles, BONE-GROWTH, Cell biology, TEX264, Autophagy & Cell Death, AUTOPHAGY, Signal transduction, 030217 neurology & neurosurgery
Abstract

Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER‐phagy) is emerging as a critical regulator of cell homeostasis and function. The recent identification of ER‐phagy receptors has shed light on the molecular mechanisms underlining this process. However, the signaling pathways regulating ER‐phagy in response to cellular needs are still largely unknown. We found that the nutrient responsive transcription factors TFEB and TFE3—master regulators of lysosomal biogenesis and autophagy—control ER‐phagy by inducing the expression of the ER‐phagy receptor FAM134B. The TFEB/TFE3‐FAM134B axis promotes ER‐phagy activation upon prolonged starvation. In addition, this pathway is activated in chondrocytes by FGF signaling, a critical regulator of skeletal growth. FGF signaling induces JNK‐dependent proteasomal degradation of the insulin receptor substrate 1 (IRS1), which in turn inhibits the PI3K‐PKB/Akt‐mTORC1 pathway and promotes TFEB/TFE3 nuclear translocation and enhances FAM134B transcription. Notably, FAM134B is required for protein secretion in chondrocytes, and cartilage growth and bone mineralization in medaka fish. This study identifies a new signaling pathway that allows ER‐phagy to respond to both metabolic and developmental cues., Nuclear translocation of TFEB/TFE3 transcription factors and expression of FAM134B downstream of FGF18 signalling induce ER‐phagy in chondrocytes to promote bone development.

Published
2020

35. Intercalated Cell Depletion and Vacuolar H + -ATPase Mistargeting in an Ae1 R607H Knockin Model

Author

Francesco Trepiccione, Seth L. Alper, Nicolas Picard, Emmanuelle Cordat, A.K.M. Shahid Ullah, Bettina Serbin, J. Christopher Hennings, Teodor G. Păunescu, Diane E. Capen, Dominique Eladari, Rizwan Mumtaz, Dennis Brown, Christian A. Hübner, Isabelle Mouro-Chanteloup, Rawad Lashhab, Carsten A. Wagner, Antje K. Huebner, Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Cardio-Thoracic and Respiratory Science, Second University of Naples, Naples, Italy, Laboratoire de Biologie Tissulaire et d'ingénierie Thérapeutique UMR 5305 (LBTI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Department of Physiology, University of Alberta, Edmonton, Alberta, Canada, Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital, Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS)-Harvard Medical School [Boston] (HMS), Institut National de la Transfusion Sanguine [Paris] (INTS), Nephrology Division and Vascular Biology Research Center, Beth Israel DeaconessMedical Center, Department of Medicine, HarvardMedical School, Boston,Massachusetts, Institute of Physiology, University of Zurich, Zurich, Switzerland, Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Picard, Nicolas, University of Alberta, Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Zurich, Eladari, Dominique, Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Physiologie Explorations Fonctionnelles Rénales, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Mumtaz, Rizwan, Trepiccione, Francesco, Hennings, J. Christopher, Huebner, Antje K, Serbin, Bettina, Picard, Nicola, Ullah, A. K. M. Shahid, Păunescu, Teodor G, Capen, Diane E, Lashhab, Rawad M, Mouro Chanteloup, Isabelle, Alper, Seth L, Wagner, Carsten A, Cordat, Emmanuelle, Brown, Denni, Hübner, Christian A., Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and ††Nephrology Division and Vascular Biology Research Center, Beth Israel DeaconessMedical Center, Department of Medicine, HarvardMedical School, Boston,Massachusetts, Institut National de la Transfusion Sanguine, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé 1134, Laboratory of Excellence Globule Rouge- Excellence, Paris Diderot University, Paris, France, Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), Diabète athérothrombose et thérapies Réunion Océan Indien ( DéTROI ), Université de la Réunion ( UR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, 0301 basic medicine, distal tubule, Vacuolar Proton-Translocating ATPases, chronic metabolic acidosis, ATPase, [SDV]Life Sciences [q-bio], Mutant, 030232 urology & nephrology, 610 Medicine & health, Biology, Models, Biological, 10052 Institute of Physiology, Cell & Transport Physiology, ion transport, Mice, 03 medical and health sciences, 0302 clinical medicine, Distal renal tubular acidosis, Mutant protein, Anion Exchange Protein 1, Erythrocyte, medicine, Secretion, Intercalated Cell, Kidney Tubules, Collecting, 2727 Nephrology, [ SDV ] Life Sciences [q-bio], chronic metabolic acidosi, Animal, genetic renal disease, Acidosis, Renal Tubular, General Medicine, medicine.disease, Cell biology, [SDV] Life Sciences [q-bio], transgenic mouse, 030104 developmental biology, Biochemistry, Nephrology, biology.protein, 570 Life sciences, biology, Cotransporter, Intracellular
Abstract

International audience; Distal nephron acid secretion is mediated by highly specialized type A intercalated cells (A-ICs), which contain vacuolar H +-ATPase (V-type ATPase)-rich vesicles that fuse with the apical plasma membrane on demand. Intra-cellular bicarbonate generated by luminal H + secretion is removed by the basolateral anion-exchanger AE1. Chronically reduced renal acid excretion in distal renal tubular acidosis (dRTA) may lead to nephrocalcinosis and renal failure. Studies in MDCK monolayers led to the proposal of a dominant-negative trafficking mechanism to explain AE1-associated dominant dRTA. To test this hypothesis in vivo, we generated an Ae1 R607H knockin mouse, which corresponds to the most common dominant dRTA mutation in human AE1, R589H. Compared with wild-type mice, heterozygous and homozygous R607H knockin mice displayed incomplete dRTA characterized by compensatory upregulation of the Na + /HCO 3 2 cotransporter NBCn1. Red blood cell Ae1-mediated anion-exchange activity and surface polypeptide expression did not change. Mutant mice expressed far less Ae1 in A-ICs, but basolateral targeting of the mutant protein was preserved. Notably, mutant mice also exhibited reduced expression of V-type ATPase and compromised targeting of this proton pump to the plasma membrane upon acid challenge. Accumulation of p62-and ubiquitin-positive material in A-ICs of knockin mice suggested a defect in the degradative pathway, which may explain the observed loss of A-ICs. R607H knockin did not affect type B intercalated cells. We propose that reduced basolateral anion-exchange activity in A-ICs inhibits trafficking and regulation of V-type ATPase, compromising luminal H + secretion and possibly lysosomal acidification.

Published
2017

36. Regulation of endoplasmic reticulum turnover by selective autophagy

Author

Paolo Grumati, Fulvio Reggiori, Muriel Mari, Aliaksandr Khaminets, Mario Mauthe, Antje K. Huebner, Britta Qualmann, Theresa Heinrich, Masato Akutsu, Nicole Koch, Sandor Nietzsche, Ingo Kurth, Ivan Dikic, Istvan Katona, Joachim Weis, Lutz Liebmann, Alexandra Stolz, Christian A. Hübner, Microbes in Health and Disease (MHD), Center for Liver, Digestive and Metabolic Diseases (CLDM), Khaminets, Aliaksandr, Heinrich, Theresa, Mari, Muriel, Grumati, Paolo, Huebner, Antje K, Akutsu, Masato, Liebmann, Lutz, Stolz, Alexandra, Nietzsche, Sandor, Koch, Nicole, Mauthe, Mario, Katona, Istvan, Qualmann, Britta, Weis, Joachim, Reggiori, Fulvio, Kurth, Ingo, Hübner, Christian A, and Dikic, Ivan

Subjects
Nucleophagy, Male, PROTEIN, Apoptosis, Biomarkers/metabolism, Lysosomes/metabolism, Endoplasmic Reticulum, Mice, Phagosomes, Non-U.S. Gov't, PHOSPHORYLATION, Membrane Protein, Phagosome, Sensory Receptor Cells/metabolism, Apoptosis Regulatory Protein, Multidisciplinary, Research Support, Non-U.S. Gov't, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, LOCALIZATION, Lysosome, Endoplasmic Reticulum/chemistry, Cell biology, Neoplasm Proteins, Biochemistry, Microtubule-Associated Proteins/metabolism, MACHINERY, Female, Autophagy/physiology, Microtubule-Associated Proteins, Human, Protein Binding, Phagosomes/metabolism, Membrane Proteins/deficiency, Sensory Receptor Cells, GABARAP, Reticulophagy, Editorials: Cell Cycle Features, Biology, Research Support, Cell Line, Neoplasm Protein, Neoplasm Proteins/deficiency, Autophagy, Journal Article, Animals, Humans, Endomembrane system, Adaptor Proteins, Signal Transducing, Animal, Endoplasmic reticulum, Microtubule-Associated Protein, Signal Transducing, Apoptosi, Membrane Proteins, Biomarker, DEGRADATION, SALMONELLA, Adaptor Proteins, Signal Transducing/metabolism, Ion homeostasis, ER, Intracellular Signaling Peptides and Protein, Reticulon, CELLS, Apoptosis Regulatory Proteins, Lysosomes, Biomarkers, Gene Deletion
Abstract

The endoplasmic reticulum (ER) is the largest intracellular endomembrane system, enabling protein and lipid synthesis, ion homeostasis, quality control of newly synthesized proteins and organelle communication(1). Constant ER turnover and modulation is needed to meet different cellular requirements and autophagy has an important role in this process(2-8). However, its underlying regulatory mechanisms remain unexplained. Here we show that members of the FAM134 reticulon protein family are ER-resident receptors that bind to autophagy modifiers LC3 and GABARAP, and facilitate ER degradation by autophagy ('ER-phagy'). Downregulation of FAM134B protein in human cells causes an expansion of the ER, while FAM134B overexpression results in ER fragmentation and lysosomal degradation. Mutant FAM134B proteins that cause sensory neuropathy in humans(9) are unable to act as ER-phagy receptors. Consistently, disruption of Fam134b in mice causes expansion of the ER, inhibits ER turnover, sensitizes cells to stress-induced apoptotic cell death and leads to degeneration of sensory neurons. Therefore, selective ER-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover in mice and humans.

Published
2015

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