Protein transport and secretion

Head of Unit

Roberto Sitia

Over the last decade, the lab focused on two tightly related problems, the pathophysiology of lymphocyte 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 the group discovered a dozen years ago, which is involved in the assembly and quality control of polymeric IgM and the biogenesis and homeostatic control of the endoplasmic reticulum and secretory organelles.

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Selected publications

Pasalic D, Weber B, Giannone C, Anelli T, Müller R, Fagioli C, Felkl M, John C, Mossuto MF, Becker CFW, Sitia R, Buchner J. A peptide extension dictates IgM assembly. Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8575-E8584.

Watanabe S, Harayama M, Kanemura S, Sitia R, Inaba K. Structural basis of pH-dependent client binding by ERp44, a key regulator of protein secretion at the ER-Golgi interface. Proc Natl Acad Sci U S A. 2017 Apr 18;114(16):E3224-E3232.

Yoboue ED, Rimessi A, Anelli T, Pinton P, Sitia R. Regulation of Calcium Fluxes by GPX8, a Type-II Transmembrane Peroxidase Enriched at the Mitochondria-Associated Endoplasmic Reticulum Membrane. Antioxid Redox Signal. 2017 Sep 20;27(9):583-595.

Giannone C, Fagioli C, Valetti C, Sitia R, Anelli T. Roles of N-glycans in the polymerization-dependent aggregation of mutant Ig-μ chains in the early secretory pathway. Sci Rep. 2017 Feb 3;7:41815.

Bertolotti M, Farinelli G, Galli M, Aiuti A, Sitia R. AQP8 transports NOX2- generated H2O2 across the plasma membrane to promote signaling in B cells. J Leukoc Biol. 2016 Nov;100(5):1071-1079.

Medraño-Fernandez I, Bestetti S, Bertolotti M, Bienert GP, Bottino C, Laforenza U, Rubartelli A, Sitia R. Stress Regulates Aquaporin-8 Permeability to Impact Cell Growth and Survival. Antioxid Redox Signal. 2016 Jun 20;24(18):1031-44

Mossuto MF, Ami D, Anelli T, Fagioli C, Doglia SM, Sitia R. Biochemical nature of Russell Bodies. Sci Rep. 2015 Jul 30;5:12585.

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 Oct 1; 127(19):4260-4269.

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 Jun 27;50(6):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. Traffic 2010 May;11(5):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 Mar 26;113(13):3040-9.

Wang L, Wang L, Vavassori S, Li S, Ke H, Anelli T, Degano M, Ronzoni R, Sitia R, Sun F and Wang CC. Crystal structure of human ERp44 reveals a dynamic functional modulation by its C-terminal tail. EMBO Rep. 2008 Jul; 9(7): 642–647.

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 Oct 3; 26(19): 4177–4188.