19 results on '"Borgese, Nica"'
Search Results
2. Selenoprotein N is an endoplasmic reticulum calcium sensor that links luminal calcium levels to a redox activity
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Chernorudskiy, Alexander, Varone, Ersilia, Colombo, Sara Francesca, Fumagalli, Stefano, Cagnotto, Alfredo, Cattaneo, Angela, Briens, Mickael, Baltzinger, Mireille, Kuhn, Lauriane, Bachi, Angela, Berardi, Andrea, Salmona, Mario, Musco, Giovanna, Borgese, Nica, Lescure, Alain, and Zito, Ester
- Published
- 2020
3. Combined Presence in Heterozygosis of Two Variant Usher Syndrome Genes in Two Siblings Affected by Isolated Profound Age-Related Hearing Loss.
- Author
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Borgese, Nica, Guillén-Samander, Andrés, Colombo, Sara Francesca, Mancassola, Giulia, Di Berardino, Federica, Zanetti, Diego, and Carrera, Paola
- Subjects
USHER'S syndrome ,HEREDITY ,HEARING disorders ,PRESBYCUSIS ,SENSORINEURAL hearing loss ,MEDICAL genetics - Abstract
Sensorineural age-related hearing loss affects a large proportion of the elderly population, and has both environmental and genetic causes. Notwithstanding increasing interest in this debilitating condition, the genetic risk factors remain largely unknown. Here, we report the case of two sisters affected by isolated profound sensorineural hearing loss after the age of seventy. Genomic DNA sequencing revealed that the siblings shared two monoallelic variants in two genes linked to Usher Syndrome (USH genes), a recessive disorder of the ear and the retina: a rare pathogenic truncating variant in USH1G and a previously unreported missense variant in ADGRV1. Structure predictions suggest a negative effect on protein stability of the latter variant, allowing its classification as likely pathogenic according to American College of Medical Genetics criteria. Thus, the presence in heterozygosis of two recessive alleles, which each cause syndromic deafness, may underlie digenic inheritance of the age-related non-syndromic hearing loss of the siblings, a hypothesis that is strengthened by the knowledge that the two genes are integrated in the same functional network, which underlies stereocilium development and organization. These results enlarge the spectrum and complexity of the phenotypic consequences of USH gene mutations beyond the simple Mendelian inheritance of classical Usher syndrome. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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4. The WRB Subunit of the Get3 Receptor is Required for the Correct Integration of its Partner CAML into the ER
- Author
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Carvalho, Hugo J. F., Del Bondio, Andrea, Maltecca, Francesca, Colombo, Sara F., and Borgese, Nica
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- 2019
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5. Discrimination between the endoplasmic reticulum and mitochondria by spontaneously inserting tail‐anchored proteins
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Figueiredo Costa, Bruna, Cassella, Patrizia, Colombo, Sara F., and Borgese, Nica
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- 2018
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6. Mutant VAPB: Culprit or Innocent Bystander of Amyotrophic Lateral Sclerosis?
- Author
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Borgese, Nica, Navone, Francesca, Nukina, Nobuyuki, and Yamanaka, Tomoyuki
- Abstract
Nearly twenty years ago a mutation in the VAPB gene, resulting in a proline to serine substitution (p.P56S), was identified as the cause of a rare, slowly progressing, familial form of the motor neuron degenerative disease Amyotrophic Lateral Sclerosis (ALS). Since then, progress in unravelling the mechanistic basis of this mutation has proceeded in parallel with research on the VAP proteins and on their role in establishing membrane contact sites between the ER and other organelles. Analysis of the literature on cellular and animal models reviewed here supports the conclusion that P56S-VAPB, which is aggregation-prone, non-functional and unstable, is expressed at levels that are insufficient to support toxic gain-of-function or dominant negative effects within motor neurons. Instead, insufficient levels of the product of the single wild-type allele appear to be required for pathological effects, and may be the main driver of the disease. In light of the multiple interactions of the VAP proteins, we address the consequences of specific VAPB depletion and highlight various affected processes that could contribute to motor neuron degeneration. In the future, distinction of specific roles of each of the two VAP paralogues should help to further elucidate the basis of p.P56S familial ALS, as well as of other more common forms of the disease. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
7. Searching for remote homologs of CAML among eukaryotes.
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Borgese, Nica
- Subjects
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BASIC proteins , *ENDOPLASMIC reticulum , *ANIMALS - Abstract
The tryptophan rich basic protein/calcium signal‐modulating cyclophilin ligand (WRB/CAML) and Get1p/Get2p complexes, in vertebrates and yeast, respectively, mediate the final step of tail‐anchored protein insertion into the endoplasmic reticulum membrane via the Get pathway. While WRB appears to exist in all eukaryotes, CAML homologs were previously recognized only among chordates, raising the question as to how CAML's function is performed in other phyla. Furthermore, whereas WRB was recognized as the metazoan homolog of Get1, CAML and Get2, although functionally equivalent, were not considered to be homologous. CAML contains an N‐terminal basic, TRC40/Get3‐interacting, region, three transmembrane segments near the C‐terminus, and a poorly conserved region between these domains. Here, I searched the NCBI protein database for remote CAML homologs in all eukaryotes, using position‐specific iterated‐basic local alignment search tool, with the C‐terminal, the N‐terminal or the full‐length sequence of human CAML as query. The N‐terminal basic region and full‐length CAML retrieved homologs among metazoa, plants and fungi. In the latter group several hits were annotated as GET2. The C‐terminal query did not return entries outside of the animal kingdom, but did retrieve over one hundred invertebrate metazoan CAML‐like proteins, which all conserved the N‐terminal TRC40‐binding domain. The results indicate that CAML homologs exist throughout the eukaryotic domain of life, and suggest that metazoan CAML and yeast GET2 share a common evolutionary origin. They further reveal a tight link between the particular features of the metazoan membrane‐anchoring domain and the TRC40‐interacting region. The list of sequences presented here should provide a useful resource for future studies addressing structure‐function relationships in CAML proteins. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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8. The GET pathway can increase the risk of mitochondrial outer membrane proteins to be mistargeted to the ER.
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Vitali, Daniela G., Sinzel, Monika, Bulthuis, Elianne P., Kolb, Antonia, Zabel, Susanne, Mehlhorn, Dietmar G., Figueiredo Costa, Bruna, Farkas, Ákos, Clancy, Anne, Schuldiner, Maya, Grefen, Christopher, Schwappach, Blanche, Borgese, Nica, and Rapaport, Doron
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MITOCHONDRIAL proteins ,ENDOPLASMIC reticulum ,GENETIC overexpression - Abstract
Tail-anchored (TA) proteins are anchored to their corresponding membrane via a single transmembrane segment (TMS) at their Cterminus. In yeast, the targeting of TA proteins to the endoplasmic reticulum (ER) can be mediated by the guided entry of TA proteins (GET) pathway, whereas it is not yet clear how mitochondrial TA proteins are targeted to their destination. It has been widely observed that some mitochondrial outer membrane (MOM) proteins are mistargeted to the ER when overexpressed or when their targeting signal is masked. However, the mechanism of this erroneous sorting is currently unknown. In this study, we demonstrate the involvement of the GET machinery in the mistargeting of suboptimalMOMproteins to the ER. These findings suggest that the GET machinery can, in principle, recognize and guide mitochondrial and non-canonical TA proteins. Hence, under normal conditions, an active mitochondrial targeting pathway must exist that dominates the kinetic competition against other pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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9. Getting membrane proteins on and off the shuttle bus between the endoplasmic reticulum and the Golgi complex.
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Borgese, Nica
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PROTEIN transport , *MEMBRANE proteins , *ENDOPLASMIC reticulum , *GOLGI apparatus , *COATED vesicles , *INTERMOLECULAR interactions - Abstract
Secretory proteins exit the endoplasmic reticulum (ER) in coat protein complex II (COPII)-coated vesicles and then progress through the Golgi complex before delivery to their final destination. Soluble cargo can be recruited to ER exit sites by signal-mediated processes (cargo capture) or by bulk flow. For membrane proteins, a third mechanism, based on the interaction of their transmembrane domain (TMD) with lipid microdomains, must also be considered. In this Commentary, I review evidence in favor of the idea that partitioning of TMDs into bilayer domains that are endowed with distinct physico-chemical properties plays a pivotal role in the transport of membrane proteins within the early secretory pathway. The combination of such selforganizational phenomena with canonical intermolecular interactions is most likely to control the release of membrane proteins from the ER into the secretory pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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10. Autophagy and Neurodegeneration: Insights from a Cultured Cell Model of ALS.
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Navone, Francesca, Genevini, Paola, and Borgese, Nica
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AUTOPHAGY ,DEGENERATION (Pathology) ,HUMAN heredity ,AMYOTROPHIC lateral sclerosis ,NEURODEGENERATION - Abstract
Autophagy plays a major role in the elimination of cellular waste components, the renewal of intracellular proteins and the prevention of the build-up of redundant or defective material. It is fundamental for the maintenance of homeostasis and especially important in post-mitotic neuronal cells, which, without competent autophagy, accumulate protein aggregates and degenerate. Many neurodegenerative diseases are associated with defective autophagy; however, whether altered protein turnover or accumulation of misfolded, aggregate-prone proteins is the primary insult in neurodegeneration has long been a matter of debate. Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by selective degeneration of motor neurons. Most of the ALS cases occur in sporadic forms (SALS), while 10%-15% of the cases have a positive familial history (FALS). The accumulation in the cell of misfolded/abnormal proteins is a hallmark of both SALS and FALS, and altered protein degradation due to autophagy dysregulation has been proposed to contribute to ALS pathogenesis. In this review, we focus on the main molecular features of autophagy to provide a framework for discussion of our recent findings about the role in disease pathogenesis of the ALS-linked form of the VAPB gene product, a mutant protein that drives the generation of unusual cytoplasmic inclusions. [ABSTRACT FROM AUTHOR]
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- 2015
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11. Amyotrophic Lateral Sclerosis-Linked Mutant VAPB Inclusions Do Not Interfere with Protein Degradation Pathways or Intracellular Transport in a Cultured Cell Model.
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Genevini, Paola, Papiani, Giulia, Ruggiano, Annamaria, Cantoni, Lavinia, Navone, Francesca, and Borgese, Nica
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AMYOTROPHIC lateral sclerosis ,VESICULAR stomatitis ,GLYCOPROTEINS ,UBIQUITIN ,MOTOR neurons ,NEUROLOGY - Abstract
VAPB is a ubiquitously expressed, ER-resident adaptor protein involved in interorganellar lipid exchange, membrane contact site formation, and membrane trafficking. Its mutant form, P56S-VAPB, which has been linked to a dominantly inherited form of Amyotrophic Lateral Sclerosis (ALS8), generates intracellular inclusions consisting in restructured ER domains whose role in ALS pathogenesis has not been elucidated. P56S-VAPB is less stable than the wild-type protein and, at variance with most pathological aggregates, its inclusions are cleared by the proteasome. Based on studies with cultured cells overexpressing the mutant protein, it has been suggested that VAPB inclusions may exert a pathogenic effect either by sequestering the wild-type protein and other interactors (loss-of-function by a dominant negative effect) or by a more general proteotoxic action (gain-of-function). To investigate P56S-VAPB degradation and the effect of the inclusions on proteostasis and on ER-to-plasma membrane protein transport in a more physiological setting, we used stable HeLa and NSC34 Tet-Off cell lines inducibly expressing moderate levels of P56S-VAPB. Under basal conditions, P56S-VAPB degradation was mediated exclusively by the proteasome in both cell lines, however, it could be targeted also by starvation-stimulated autophagy. To assess possible proteasome impairment, the HeLa cell line was transiently transfected with the ERAD (ER Associated Degradation) substrate CD3δ, while autophagic flow was investigated in cells either starved or treated with an autophagy-stimulating drug. Secretory pathway functionality was evaluated by analyzing the transport of transfected Vesicular Stomatitis Virus Glycoprotein (VSVG). P56S-VAPB expression had no effect either on the degradation of CD3δ or on the levels of autophagic markers, or on the rate of transport of VSVG to the cell surface. We conclude that P56S-VAPB inclusions expressed at moderate levels do not interfere with protein degradation pathways or protein transport, suggesting that the dominant inheritance of the mutant gene may be due mainly to haploinsufficiency. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
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12. A positive signal prevents secretory membrane cargo from recycling between the Golgi and the ER.
- Author
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Fossati, Matteo, Colombo, Sara F, and Borgese, Nica
- Subjects
GOLGI apparatus ,CELLULAR signal transduction ,CELL membranes ,ENDOPLASMIC reticulum ,MEMBRANE proteins - Abstract
The Golgi complex and ER are dynamically connected by anterograde and retrograde trafficking pathways. To what extent and by what mechanism outward-bound cargo proteins escape retrograde trafficking has been poorly investigated. Here, we analysed the behaviour of several membrane proteins at the ER/Golgi interface in live cells. When Golgi-to-plasma membrane transport was blocked, vesicular stomatitis virus glycoprotein ( VSVG), which bears an ER export signal, accumulated in the Golgi, whereas an export signal-deleted version of VSVG attained a steady state determined by the balance of retrograde and anterograde traffic. A similar behaviour was displayed by EGF receptor and by a model tail-anchored protein, whose retrograde traffic was slowed by addition of VSVG's export signal. Retrograde trafficking was energy- and Rab6-dependent, and Rab6 inhibition accelerated signal-deleted VSVG's transport to the cell surface. Our results extend the dynamic bi-directional relationship between the Golgi and ER to include surface-directed proteins, uncover an unanticipated role for export signals at the Golgi complex, and identify recycling as a novel factor that regulates cargo transport out of the early secretory pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
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13. The Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis.
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Borgese, Nica, Iacomino, Nicola, Colombo, Sara Francesca, and Navone, Francesca
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MOTOR neuron diseases , *INDUCED pluripotent stem cells , *MOTOR neurons , *MUTANT proteins , *AMYOTROPHIC lateral sclerosis , *ION transport (Biology) , *ADAPTOR proteins - Abstract
The VAP proteins are integral adaptor proteins of the endoplasmic reticulum (ER) membrane that recruit a myriad of interacting partners to the ER surface. Through these interactions, the VAPs mediate a large number of processes, notably the generation of membrane contact sites between the ER and essentially all other cellular membranes. In 2004, it was discovered that a mutation (p.P56S) in the VAPB paralogue causes a rare form of dominantly inherited familial amyotrophic lateral sclerosis (ALS8). The mutant protein is aggregation-prone, non-functional and unstable, and its expression from a single allele appears to be insufficient to support toxic gain-of-function effects within motor neurons. Instead, loss-of-function of the single wild-type allele is required for pathological effects, and VAPB haploinsufficiency may be the main driver of the disease. In this article, we review the studies on the effects of VAPB deficit in cellular and animal models. Several basic cell physiological processes are affected by downregulation or complete depletion of VAPB, impinging on phosphoinositide homeostasis, Ca2+ signalling, ion transport, neurite extension, and ER stress. In the future, the distinction between the roles of the two VAP paralogues (A and B), as well as studies on motor neurons generated from induced pluripotent stem cells (iPSC) of ALS8 patients will further elucidate the pathogenic basis of p.P56S familial ALS, as well as of other more common forms of the disease. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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14. Complexity and Specificity of Sec61-Channelopathies: Human Diseases Affecting Gating of the Sec61 Complex.
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Sicking, Mark, Lang, Sven, Bochen, Florian, Roos, Andreas, Drenth, Joost P. H., Zakaria, Muhammad, Zimmermann, Richard, Linxweiler, Maximilian, and Borgese, Nica
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MOLECULAR chaperones ,IMMUNOGLOBULIN heavy chains ,CARRIER proteins ,PROTEIN folding ,HOMEOSTASIS ,HISTONES ,CALCIUM metabolism ,CALCIUM channels - Abstract
The rough endoplasmic reticulum (ER) of nucleated human cells has crucial functions in protein biogenesis, calcium (Ca
2+ ) homeostasis, and signal transduction. Among the roughly one hundred components, which are involved in protein import and protein folding or assembly, two components stand out: The Sec61 complex and BiP. The Sec61 complex in the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER and provides a conduit for Ca2+ ions from the ER lumen to the cytosol. The second component, the Hsp70-type molecular chaperone immunoglobulin heavy chain binding protein, short BiP, plays central roles in protein folding and assembly (hence its name), protein import, cellular Ca2+ homeostasis, and various intracellular signal transduction pathways. For the purpose of this review, we focus on these two components, their relevant allosteric effectors and on the question of how their respective functional cycles are linked in order to reconcile the apparently contradictory features of the ER membrane, selective permeability for precursor polypeptides, and impermeability for Ca2+ . The key issues are that the Sec61 complex exists in two conformations: An open and a closed state that are in a dynamic equilibrium with each other, and that BiP contributes to its gating in both directions in cooperation with different co-chaperones. While the open Sec61 complex forms an aqueous polypeptide-conducting- and transiently Ca2+ -permeable channel, the closed complex is impermeable even to Ca2+ . Therefore, we discuss the human hereditary and tumor diseases that are linked to Sec61 channel gating, termed Sec61-channelopathies, as disturbances of selective polypeptide-impermeability and/or aberrant Ca2+ -permeability. [ABSTRACT FROM AUTHOR]- Published
- 2021
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15. Morphological Heterogeneity of the Endoplasmic Reticulum within Neurons and Its Implications in Neurodegeneration.
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Sree, Sreesha, Parkkinen, Ilmari, Their, Anna, Airavaara, Mikko, Jokitalo, Eija, and Borgese, Nica
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NEURODEGENERATION ,NEURONS ,HETEROGENEITY ,HOMEOSTASIS ,MEMBRANE proteins - Abstract
The endoplasmic reticulum (ER) is a multipurpose organelle comprising dynamic structural subdomains, such as ER sheets and tubules, serving to maintain protein, calcium, and lipid homeostasis. In neurons, the single ER is compartmentalized with a careful segregation of the structural subdomains in somatic and neurite (axodendritic) regions. The distribution and arrangement of these ER subdomains varies between different neuronal types. Mutations in ER membrane shaping proteins and morphological changes in the ER are associated with various neurodegenerative diseases implying significance of ER morphology in maintaining neuronal integrity. Specific neurons, such as the highly arborized dopaminergic neurons, are prone to stress and neurodegeneration. Differences in morphology and functionality of ER between the neurons may account for their varied sensitivity to stress and neurodegenerative changes. In this review, we explore the neuronal ER and discuss its distinct morphological attributes and specific functions. We hypothesize that morphological heterogeneity of the ER in neurons is an important factor that accounts for their selective susceptibility to neurodegeneration. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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16. Tail-anchored Protein Insertion in Mammals.
- Author
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Colombo, Sara Francesca, Cardani, Silvia, Maroli, Annalisa, Vitiello, Adriana, Soffientini, Paolo, Crespi, Arianna, Bram, Richard F., Benfante, Roberta, and Borgese, Nica
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ENDOPLASMIC reticulum , *ADENOSINE triphosphatase , *MEMBRANE proteins , *CELL culture , *LABORATORY rats - Abstract
The GET (guided entry of tail-anchored proteins)/TRC (transmembrane recognition complex) pathway for tail-anchored protein targeting to the endoplasmic reticulum (ER) has been characterized in detail in yeast and is thought to function similarly in mammals, where the orthologue of the central ATPase, Get3, is known as TRC40 or Asna1. Get3/TRC40 function requires an ER receptor, which in yeast consists of the Get1/ Get2 heterotetramer and in mammals of theWRBprotein (tryptophan- rich basic protein), homologous to yeast Get1, in combination with CAML (calcium-modulating cyclophilin ligand), which is not homologous to Get2. To better characterize the mammalian receptor, we investigated the role of endogenousWRBand CAML in tail-anchored protein insertion as well as their association, concentration, and stoichiometry in rat liver microsomes and cultured cells. Functional proteoliposomes, reconstituted from a microsomal detergent extract, lost their activity when made with an extract depleted of TRC40- associated proteins or of CAML itself, whereas in vitro synthesized CAML and WRB together were sufficient to confer insertion competence to liposomes. CAML was found to be in ~5-fold excess over WRB, and alteration of this ratio did not inhibit insertion. Depletion of each subunit affected the levels of the other one; in the case of CAML silencing, this effect was attributable to destabilization of the WRB transcript and not of WRBprotein itself. These results reveal unanticipated complexity in the mutual regulation of the TRC40 receptor subunits and raise the question as to the role of the excessCAMLin the mammalian ER. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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17. Correction: VAPB depletion alters neuritogenesis and phosphoinositide balance in motoneuron-like cells: relevance to VAPB-linked amyotrophic lateral sclerosis (doi:10.1242/jcs.220061).
- Author
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Genevini P, Colombo MN, Venditti R, Marcuzzo S, Colombo SF, Bernasconi P, De Matteis MA, Borgese N, and Navone F
- Published
- 2019
- Full Text
- View/download PDF
18. VAPB depletion alters neuritogenesis and phosphoinositide balance in motoneuron-like cells: relevance to VAPB-linked amyotrophic lateral sclerosis.
- Author
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Genevini P, Colombo MN, Venditti R, Marcuzzo S, Colombo SF, Bernasconi P, De Matteis MA, Borgese N, and Navone F
- Subjects
- Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis pathology, Animals, Golgi Apparatus metabolism, HeLa Cells, Humans, Motor Neurons pathology, Mutation, Neurites pathology, Rats, Vesicular Transport Proteins genetics, Amyotrophic Lateral Sclerosis metabolism, Endoplasmic Reticulum metabolism, Motor Neurons metabolism, Neurites metabolism, Phosphatidylinositols metabolism, Vesicular Transport Proteins metabolism
- Abstract
VAPB and VAPA are ubiquitously expressed endoplasmic reticulum membrane proteins that play key roles in lipid exchange at membrane contact sites. A mutant, aggregation-prone, form of VAPB (P56S) is linked to a dominantly inherited form of amyotrophic lateral sclerosis; however, it has been unclear whether its pathogenicity is due to toxic gain of function, to negative dominance, or simply to insufficient levels of the wild-type protein produced from a single allele (haploinsufficiency). To investigate whether reduced levels of functional VAPB, independently from the presence of the mutant form, affect the physiology of mammalian motoneuron-like cells, we generated NSC34 clones, from which VAPB was partially or nearly completely depleted. VAPA levels, determined to be over fourfold higher than those of VAPB in untransfected cells, were unaffected. Nonetheless, cells with even partially depleted VAPB showed an increase in Golgi- and acidic vesicle-localized phosphatidylinositol-4-phosphate (PI4P) and reduced neurite extension when induced to differentiate. Conversely, the PI4 kinase inhibitors PIK93 and IN-10 increased neurite elongation. Thus, for long-term survival, motoneurons might require the full dose of functional VAPB, which may have unique function(s) that VAPA cannot perform., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)
- Published
- 2019
- Full Text
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19. CAML mediates survival of Myc-induced lymphoma cells independent of tail-anchored protein insertion.
- Author
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Shing JC, Lindquist LD, Borgese N, and Bram RJ
- Abstract
Calcium-modulating cyclophilin ligand (CAML) is an endoplasmic reticulum (ER) protein that functions, along with WRB and TRC40, to mediate tail-anchored (TA) protein insertion into the ER membrane. Physiologic roles for CAML include endocytic trafficking, intracellular calcium signaling, and the survival and proliferation of specialized immune cells, recently attributed to its requirement for TA protein insertion. To identify a possible role for CAML in cancer cells, we generated Eμ-Myc transgenic mice that carry a tamoxifen-inducible deletion allele of Caml . In multiple B-cell lymphoma cell lines derived from these mice, homozygous loss of Caml activated apoptosis. Cell death was blocked by Bcl-2/Bcl-x
L overexpression; however, rescue from apoptosis was insufficient to restore proliferation. Tumors established from an Eμ-Myc lymphoma cell line completely regressed after tamoxifen administration, suggesting that CAML is also required for these cancer cells to survive and grow in vivo . Cell cycle analyses of Caml -deleted lymphoma cells revealed an arrest in G2/M, accompanied by low expression of the mitotic marker, phospho-histone H3 (Ser10). Surprisingly, lymphoma cell viability did not depend on the domain of CAML required for its interaction with TRC40. Furthermore, a small protein fragment consisting of the C-terminal 111 amino acid residues of CAML, encompassing the WRB-binding domain, was sufficient to rescue growth and survival of Caml -deleted lymphoma cells. Critically, this minimal region of CAML did not restore TA protein insertion in knockout cells. Taken together, these data reveal an essential role for CAML in supporting survival and mitotic progression in Myc-driven lymphomas that is independent of its TA protein insertion function., Competing Interests: The authors declare no conflict of interest.- Published
- 2017
- Full Text
- View/download PDF
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