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1. Selective Secretion of KDEL-Bearing Proteins: Mechanisms and Functions

Author

Palazzo, F. C., Sitia, R., and Tempio, T.

Subjects
Cell Biology, Developmental Biology
Abstract

In multicellular organisms, cells must continuously exchange messages with the right meaning, intensity, and duration. Most of these messages are delivered through cognate interactions between membrane and secretory proteins. Their conformational maturation is assisted by a vast array of chaperones and enzymes, ensuring the fidelity of intercellular communication. These folding assistants reside in the early secretory compartment (ESC), a functional unit that encompasses endoplasmic reticulum (ER), intermediate compartment and cis-Golgi. Most soluble ESC residents have C-terminal KDEL-like motifs that prevent their transport beyond the Golgi. However, some accumulate in the ER, while others in downstream stations, implying different recycling rates. Moreover, it is now clear that cells can actively secrete certain ESC residents but not others. This essay discusses the physiology of their differential intracellular distribution, and the mechanisms that may ensure selectivity of release.

Published
2022

5. Regulation of H2O2 transport across cell membranes

Author

Bienert,GP, Medraño-Fernandez,I, Sitia,R, Bienert GP, Medraño-Fernandez I, Sitia R, Margreet C M Vissers, Mark B Hampton, Tony J Kettle, Bienert, Gp, Medraño-Fernandez, I, and Sitia, R

Published
2018

9. Stress Regulates Aquaporin-8 Permeability to Impact Cell Growth and Survival

Author

Medraño Fernandez, I, Bestetti, S, Bertolotti, M, Bienert, G, Bottino, C, Laforenza, U, Rubartelli, A, Sitia, R, Sitia, R., BESTETTI, STEFANO, Medraño Fernandez, I, Bestetti, S, Bertolotti, M, Bienert, G, Bottino, C, Laforenza, U, Rubartelli, A, Sitia, R, Sitia, R., and BESTETTI, STEFANO

Abstract

Aquaporin-8 (AQP8) allows the bidirectional transport of water and hydrogen peroxide across biological membranes. Depending on its concentration, H2O2 exerts opposite roles, amplifying growth factor signaling in physiological conditions, but causing severe cell damage when in excess. Thus, H2O2 permeability is likely to be tightly controlled in living cells. Aims: In this study, we investigated whether and how the transport of H2O2 through plasma membrane AQP8 is regulated, particularly during cell stress. Results: We show that diverse cellular stress conditions, including heat, hypoxia, and ER stress, reversibly inhibit the permeability of AQP8 to H2O2 and water. Preventing the accumulation of intracellular reactive oxygen species (ROS) during stress counteracts AQP8 blockade. Once inhibition is established, AQP8-dependent transport can be rescued by reducing agents. Neither H2O2 nor water transport is impaired in stressed cells expressing a mutant AQP8, in which cysteine 53 had been replaced by serine. Cells expressing this mutant are more resistant to stress-, drug-, and radiation-induced growth arrest and death. Innovation and Conclusion: The control of AQP8-mediated H2O2 transport provides a novel mechanism to regulate cell signaling and survival during stress.

Published
2016

12. Transit of H₂O₂ across the endoplasmic reticulum membrane is not sluggish

Author

Appenzeller-Herzog, C. (Christian), Bánhegyi, G. (Gabor), Bogeski, I. (Ivan), Davies, K. J. (Kelvin J.A.), Delaunay-Moisan, A. (Agnès), Forman, H. J. (Henry Jay), Görlach, A. (Agnes), Kietzmann, T. (Thomas), Laurindo, F. (Francisco), Margittai, E. (Eva), Meyer , A. J. (Andreas J.), Riemer, J. (Jan), Rützler, M. (Michael), Simmen, T. (Thomas), Sitia, R. (Roberto), Toledano, M. B. (Michel B.), and Touw, I. P. (Ivo P.)

Abstract

Cellular metabolism provides various sources of hydrogen peroxide (H₂O₂) in different organelles and compartments. The suitability of H₂O₂ as an intracellular signaling molecule therefore also depends on its ability to pass cellular membranes. The propensity of the membranous boundary of the endoplasmic reticulum (ER) to let pass H₂O₂ has been discussed controversially. In this essay, we challenge the recent proposal that the ER membrane constitutes a simple barrier for H₂O₂ diffusion and support earlier data showing that (i) ample H₂O₂ permeability of the ER membrane is a prerequisite for signal transduction, (ii) aquaporin channels are crucially involved in the facilitation of H₂O₂ permeation, and (iii) a proper experimental framework not prone to artifacts is necessary to further unravel the role of H₂O₂ permeation in signal transduction and organelle biology.

Published
2016

13. Response to Marinelli and Marchissio

Author

Bertolotti, M, Bestetti, S, Medrano Fernandez, I, Sitia, R, Sitia, R., BESTETTI, STEFANO, Bertolotti, M, Bestetti, S, Medrano Fernandez, I, Sitia, R, Sitia, R., and BESTETTI, STEFANO

Published
2013

14. Tyrosine Kinase signal modulation: A matter of H2O2 membrane permeability?

Author

Bertolotti, M, Bestetti, S, García Manteiga, J, Medraño Fernandez, I, Dal Mas, A, Malosio, M, Sitia, R, Sitia, R., BESTETTI, STEFANO, Bertolotti, M, Bestetti, S, García Manteiga, J, Medraño Fernandez, I, Dal Mas, A, Malosio, M, Sitia, R, Sitia, R., and BESTETTI, STEFANO

Abstract

H2O2 produced by extracellular NADPH oxidases regulates tyrosine kinase signaling inhibiting phosphatases. How does it cross the membrane to reach its cytosolic targets? Silencing aquaporin-8 (AQP8), but not AQP3 or AQP4, inhibited H2O2 entry into HeLa cells. Re-expression of AQP8 with silencing-resistant vectors rescued H 2O2 transport, whereas a C173A-AQP8 mutant failed to do so. Lowering AQP8 levels affected H2O2 entry into the endoplasmic reticum, but not into mitochondria. AQP8 silencing also inhibited the H2O2 spikes and phosphorylation of downstream proteins induced by epidermal growth factor. These observations lead to the hypothesis that H2O2 does not freely diffuse across the plasma membrane and AQP8 and other H2O2 transporters are potential targets for manipulating key signaling pathways in cancer and degenerative diseases. Antioxid. Redox Signal. 19, 1447-1451. © Mary Ann Liebert, Inc.

Published
2013

18. The balance of proteasome load vs. capacity determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition

Author

BIANCHI G, OLIVA O, PAOLO CASCIO P, PENGO N, FONTANA F, CERRUTI F, ORSI A, PASQUALETTO E, MEZGHRANI A, CALBI V, PALLADINI G, GIULIANI N, ANDERSON KC, SITIA R, CENCI S, Bianchi, G, Oliva, O, PAOLO CASCIO, P, Pengo, N, Fontana, F, Cerruti, F, Orsi, A, Pasqualetto, E, Mezghrani, A, Calbi, V, Palladini, G, Giuliani, N, Anderson, Kc, Sitia, R, and Cenci, S

Subjects
PROTEOSTASIS, MYELOMA, PROTEASOME INHIBITORS
Abstract

Proteasome inhibitors (PIs) are effective against multiple myeloma (MM), but the mechanisms of action and bases of individual susceptibility remain unclear. Recent work linked PI sensitivity to protein synthesis and proteasome activity, raising the question whether different levels of proteasome expression and workload underlie PI sensitivity inMMcells (MMCs). Exploiting human MM lines characterized by differential PI sensitivity, we reportthat highly sensitive MMCs express lower proteasome levels and higher proteasomal workload than relatively PI-resistant MMCs, resulting in the accumulation of polyubiquitinated proteins at the expense of free ubiquitin (proteasome stress). Manipulating proteasome expression or workload alters apoptotic sensitivity to PI, demonstrating a cause-effect relationship between proteasome stress and apoptotic responses in MMCs. Intracellular immunostaining in primary, patient-derived MMCs reveals that polyubiquitinated proteins hallmark neoplastic plasmacells, in positive correlation with immunoglobulin (Ig) content, both intra- and interpatient. Moreover, overall proteasome activity of primary MMCs inversely correlates with apoptotic sensitivity to PI. Altogether,our data indicate that the balance between proteasome workload and degradative capacity represents a critical determinant of apoptotic sensitivity of MMCs to PI, potentially providing a framework for identifying indicators of responsiveness and designing novel combination therapies. (Blood. 2009;113:3040-3049)

Published
2009

19. Controllo dell'espressione genica

Author

Amicone, L, Battaglioli, E, Bonaldo, P, Bonfanti, P, Braghetta, P, Camaioni, A, Colombo, A, Dalle Donne, I, Duga, S, Gangitano, C, Garbi, C, Limonta, P, Marini, M, Moretti, R, Poletti, A, Sidoti, A, Sitia, R, Strippoli, R, and Zalfa, F

Subjects
Settore BIO/17
Published
2014

26. Ero1-PDI interactions, the response to redox flux and the implications for disulfide bond formation in the mammalian endoplasmic reticulum

Author

Benham, A.M., Lith, M. van, Sitia, R., Braakman, I., Cellular Protein Chemistry, Chemie van glyco-conjugaten, Dep Scheikunde, Sub Cellular Protein Chemistry, Benham, Am, van Lith, M, Sitia, Roberto, Braakman, I., Cellular Protein Chemistry, Chemie van glyco-conjugaten, Dep Scheikunde, and Sub Cellular Protein Chemistry

Subjects
Redox Disulfide bond, DNA, Complementary, Protein Disulfide-Isomerases, Chaperone, Endoplasmic Reticulum, Redox, General Biochemistry, Genetics and Molecular Biology, Cell Line, redox regulation, 03 medical and health sciences, 0302 clinical medicine, ER oxidoreductin, protein folding, protein secretion, chaperone, Animals, Humans, Disulfides, Protein folding, Protein disulfide-isomerase, Secretory pathway, 030304 developmental biology, Mammals, chemistry.chemical_classification, 0303 health sciences, Membrane Glycoproteins, biology, Chemistry, Endoplasmic reticulum, Articles, Electron acceptor, Cell biology, Gene Expression Regulation, redox, Chaperone (protein), oxidative folding, biology.protein, Biophysics, disulfide bond, Oxidoreductases, General Agricultural and Biological Sciences, Oxidation-Reduction, 030217 neurology & neurosurgery, Research Article, Molecular Chaperones
Abstract

The protein folding machinery of the endoplasmic reticulum (ER) ensures that proteins entering the eukaryotic secretory pathway acquire appropriate post-translational modifications and reach a stably folded state. An important component of this protein folding process is the supply of disulfide bonds. These are introduced into client proteins by ER resident oxidoreductases, including ER oxidoreductin 1 (Ero1). Ero1 is usually considered to function in a linear pathway, by ‘donating’ a disulfide bond to protein disulfide isomerase (PDI) and receiving electrons that are passed on to the terminal electron acceptor molecular oxygen. PDI engages with a range of clients as the direct catalyst of disulfide bond formation, isomerization or reduction. In this paper, we will consider the interactions of Ero1 with PDI family proteins and chaperones, highlighting the effect that redox flux has on Ero1 partnerships. In addition, we will discuss whether higher order protein complexes play a role in Ero1 function.

Published
2013

28. Neurodegeneration

Author

Milardi, D, Rizzarelli, Enrico, Williams, R. J. P., FRAUSTO DA SILVA, J. J. R., Saaranen, M. J., Ruddock, L. W., Cenci, S, Sitia, R, Kagan, B. L., Grasso, Giuseppe, LA MENDOLA, D, Amadoro, G, Calissano, P, Rembach, A, Duce, J. A., O'Sullivan, L. A., Tanzi, R. E., Bush, A. I., Zucca, F. A., Cupaioli, f. a., Zecca, L, Bolognin, S, Zatta, P, Lelie, H. L., Whitelegge, J. P., Borchelt, D. R., Valentine, J. S., and Millhauser, G. L.

Subjects
Proteostasis, Neurodegeneration, medicine, Biology, medicine.disease, Neuroscience
Published
2011

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