Protein transport and secretion

Roberto Sitia, Head of Unit

Over the last decade, the lab focused on two tightly related problems, the pathophysiology of B to plasma cell development and redox regulation/signaling in the early secretory pathway. Important traits d’union between the two are ERp44, a multifunctional chaperone we discovered a dozen years ago (Anelli et al., 2002, 2003 EMBO J), the assembly and quality control of polymeric IgM and the biogenesis and homeostatic control of the endoplasmic reticulum and secretory organelles.

Selected publications

Sannino S, Anelli T, Cortini M, Masui S, Degano M, Fagioli C, Inaba K and Sitia R. Progressive quality control in the early secretory compartment by ERp44. J Cell Sci. 2014 Aug

Vavassori S, Cortini M. Masui S, Sannino S. Anelli T. Caserta I, Fagioli C, Mossuto MF, Fornili A. van Anken Degano M, Inaba K and Sitia R. A pH-regulated quality control cycle for surveillance of secretory protein assembly. Molecular Cell. 2013. 50:783-92

Pengo N, Scolari M, Oliva L, Milan E, Mainoldi F, Raimondi A, Fagioli C, Merlini A, Mariani E, Pasqualetto E, Orfanelli U, Ponzoni M, Sitia R, Casola S, Cenci S. Plasma cells require autophagy for sustainable immunoglobulin production. Nature Immunol. 2013. 14:298-305

Anelli T, Bergamelli L, Rimessi A, Fagioli C, Malgaroli A, Pinton P, Ripamonti M, Rizzuto R and Sitia R. Ero1a regulates Ca2+ fluxes at the endoplasmic reticulum-mitochondria interface (MAM). Antioxid. Redox Signal. 2012. 16, 1007-87

Cortini M and Sitia R. ERp44 andERGIC-53 synergize in coupling efficiency and fidelity of IgM polymerization and secretion. 2010. Traffic. 11,651-659

Bianchi G, Oliva L, 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*. The proteasome load vs.capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition. Blood. 2009. 113, 3040-9. * joint last authors

Wang L, Wang L, Vavassori S, Li S, Ke H, Anelli T, Degano M, Ronzoni R, Sitia R*, Sun F* & Wang CC*. Crystal structure of human ERp44 reveals a dynamic functional modulation by its C-terminal tail. EMBO Rep. 2008. 9, 642-7 *, joint last authors

Anelli T, Ceppi S, Bergamelli L, Cortini M, Masciarelli S, Valetti C and Sitia R. Sequential steps and checkpoints in the early exocytic compartment during secretory IgM biogenesis. EMBO J. 2007. 26, 4177-88

Cenci S, Mezghrani A, Cascio P, Bianchi G, Cerruti F, Fra A, Lelouard H, Masciarelli S, Mattioli L, Oliva L, Orsi A, Pasqualetto E, Pierre P, Ruffato E, Tagliavacca L and Sitia, R. Progressively impaired proteasomal capacity during terminal plasma cell differentiation. EMBO J. 2006. 25, 1104-1113

Orsi A, Fioriti L, Chiesa R, Sitia R. Conditions of endoplasmic reticulum stress favor the accumulation of cytosolic prion protein. J Biol Chem. 2006. 281, 30431-8

Nerini-Molteni SN, Fassio A, Ciriolo MR, Filomeni G, Pasqualetto E, Fagioli C, Sitia R. Glutathione limits Ero1-dependent oxidation in the endoplasmic reticulum. J Biol Chem. 2004. 279, 32667-73

van Anken E, Romijn EP, Maggioni C, Mezghrani A, Sitia R*, Braakman I*, and Heck AJR*. Sequential waves of functionally related proteins are expressed when B cells prepare for antibody secretion. Immunity. 2003. 18, 243-53. * joint last authors

Anelli T., Alessio M., Mezghrani A., Simmen T., Talamo F., Bachi A., Sitia R. ERp44, a novel endoplasmic reticulum folding assistant of the thioredoxin family. EMBO J. 2002. 21, 835

Mezghrani A, Fassio A, Benham A, Simmen T, Braakman I, Sitia R. Manipulation of Oxidative Protein Folding and PDI Redox State in Mammalian Cells. EMBO J. 2001. 20, 6288

Reddy P, Sparvoli A, Fagioli C, Fassina G and Sitia R. Formation of reversible disulfide bonds with the protein matrix of the endoplasmic reticulum correlates with the retention of unassembled Ig-light chains. EMBO J. 1996. 15, 2077-2085

Rubartelli A, Bajetto A, Allavena G, Wollman E and Sitia R. Secretion of thioredoxin by normal and neoplastic cells through a leaderless secretory pathway. J Biol Chem. 1992. 267, 24161-24164

Valetti C, Grossi CE, Milstein C and Sitia R. Russell bodies: a general response of secretory cells to synthesis of a mutant immunoglobulin which can neither exit from, nor be degraded in, the endoplasmic reticulum. J Cell Biol. 1991. 115, 983-994

Sitia R, Neuberger MS, Alberini C, Bet P, Fra AM, Valetti C, Williams G and Milstein C. Developmental regulation of IgM secretion: the role of the carboxy-terminal cysteine. Cell. 1990. 60, 781-790

Alberini CM, Bet P, Milstein C, Sitia R. Secretion of immunoglobulin M assembly intermediates in the presence of reducing agents. Nature. 1990. 347:485-7

Klausner RD, and Sitia R. Protein degradation in the endoplasmic reticulum. Cell. 1990. 62, 611-614

Stavnezer J, Radcliffe G, Lin YC, Nietupski J, Berggren L, Sitia R, and Severinson E. Ig heavy chain switching may be directed by prior induction of transcripts from constant region genes. Proc Natl Acad Sci USA. 1988. 85, 7704-7708

Sitia R, Neuberger MS, and Milstein C. Regulation of membrane IgM expression in secretory B cells: translational and posttranslational events. EMBO J. 1987. 6, 3969-3977

Sitia R, Corte G, Ferrarini M, and Bargellesi A. Lymphocyte membrane immunoglobulins: similarities between human IgD and mouse IgD-like molecules. Eur J Immunol. 1977. 7, 503-507

Monographs and review articles

Kakihana T, Nagata K, Sitia R. Peroxides and peroxidases in the endoplasmic reticulum: integrating redox homeostasis and oxidative folding. Antioxid Redox Signal. 2012. 15:763-71

Cenci S, Van Anken E and Sitia R. Proteostenosis and plasma cell pathophysiology. Curr Opin Cell Biol. 2011. 23, 216-222

Anelli T and Sitia R. Physiology and pathology of proteostasis in the early secretory compartment. Semin Cell Dev Biol. 2010. 21:520-5

Rubartelli A and Sitia R. Stress as an intercellular signal: the emergence os stress associated molecular patterns (SAMP). Antioxid Redox Signal. 2009. 11:2621-9

Anelli T and Sitia R. Protein quality control in the early secretory pathway. EMBO J. 2008. 27,315-27

Cenci S and Sitia R. Managing andexploiting stress in the antibody factory. FEBS Lett. 2007. 581,3652-7.

Sitia R, Nerini-Molteni SN. Stress, protein (mis)folding, and signaling: the redox connection. Science STKE. 2004. 239, 27

Sitia R and Braakman I. Quality control in the endoplasmic reticulum protein factory. Nature. 2003. 426, 891-4


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