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In the early secretory pathway, stringent quality control mechanisms ensure that only properly folded and assembled proteins can proceed downstream the ER to be finally secreted; non correctly folded or non-completely assembled peptides are instead intracellularly retained and eventually degraded. Two quality control check points exist, sequential in time and space: one is located in the ER and mediated by ER resident chaperones such as BiP, the other is downstream, in the ERGCI-cisGolgi region. I isolated ERp44 several years ago as a partner of the ER oxidoreductase Ero1alpha (Anelli et al., 2002), and then demonstrated that ERp44 has a key role in the second QC check point (Anelli et al., 2003 and 2007). We also showed that, besides having a role in protein folding, ERp44 together with Ero1alpha can also modulate Ca2+ exit from the ER (Anelli et al., 2012). ERp44 is thus able to link protein folding, redox homeostasis and Ca2+ signalling. How can ERp44 carry out all these different functions? How is ERp44 activity modulated? Which are the physiological roles of ERp44 “in vivo”? We are trying to answer to these questions, also thanks to the availability of recently generated murine models.
The analysis on protein quality control brought me to study the aggregation of misfolded proteins is the ER (Ronzoni et al., 2010), which is responsible for the onset of ER storage disorders. Understanding how to deal with protein aggregation in the ER can be important for the cure of these diseases. To this purpose, we have analyzed, as a model of ER storage disorders, the behavior of mutant forms of the IgM heavy chain, which form protein aggregates in the early secretory pathway (Russel Bodies). By tagging the mutants IgM with the Halo tag, we have been able to visualize “in vivo” the formation and the movements of RBs inside the cells (Mossuto et al., 2014). How is the cell able to cope with the presence of these enormous structures is at the moment under analysis.
Click to see media1 (Movements of Halo-tagged Russel Bodies (one image every 5 sec)
(in collaboration with Davide Mazza, Alembic)
Publications
Mossuto MF, Sannino S, Mazza D, Fagioli C, Vitale M, Yoboue ED, Sitia R, Anelli T. A dynamic study of protein secretion and aggregation in the secretory pathway. PLoS One. 2014 Oct 3;9(10):e108496. doi: 10.1371/journal.pone.0108496. eCollection 2014.
PMID:25279560
Sannino S, Anelli T, Cortini M, Masui S, Degano M, Fagioli C, Inaba K, Sitia R. Progressive quality control of secretory proteins in the early secretory compartment by ERp44. J Cell Sci. 2014 Oct 1;127(Pt 19):4260-9. doi: 10.1242/jcs.153239. Epub 2014 Aug 5. PMID:25097228
Anelli T, van Anken E. Missing links in antibody assembly control. Int J Cell Biol. 2013;2013:606703. doi: 10.1155/2013/606703. Epub 2013 Dec 31. Review. PMID:24489546
Vavassori S, Cortini M, Masui S, Sannino S, Anelli T, Caserta IR, Fagioli C, Mossuto MF, Fornili A, van Anken E, Degano M, Inaba K, Sitia R. A pH-regulated quality control cycle for surveillance of secretory protein assembly Mol Cell. 2013 Jun 27;50(6):783-92. doi: 10.1016/j.molcel.2013.04.016. Epub 2013 May 16. Download pdf
Anelli, T., Bergamelli, L., Margittai, E., Rimessi, A., Fagioli, C., Malgaroli, A., Pinton, P., Ripamonti, M., Rizzuto, R., Sitia, R. Ero1α regulates Ca 2+ fluxes at the endoplasmic reticulum-mitochondria interface (MAM) (2012) Antioxidants and Redox Signaling, 16 (10), pp. 1077-1087.
Anelli, T., Sitia, R. Physiology and pathology of proteostasis in the early secretory compartment (2010) Seminars in Cell and Developmental Biology, 21 (5), pp. 520-525.
Ronzoni, R., Anelli, T., Brunati, M., Cortini, M., Fagioli, C., Sitia, R. Pathogenesis of ER storage disorders: Modulating russell body biogenesis by altering proximal and distal quality control (2010) Traffic, 11 (7), pp. 947-957.
Wang, L., Wang, L., Vavassori, S., Li, S., Ke, H., Anelli, T., Degano, M., Ronzoni, R., Sitia, R., Sun, F., Wang, C.-C. Crystal structure of human ERp44 shows a dynamic functional modulation by its carboxy-terminal tail (2008) EMBO Reports, 9 (7), pp. 642-647.
Anelli, T., Sitia, R. Protein quality control in the early secretory pathway (2008) EMBO Journal, 27 (2), pp. 315-327.
Anelli, T., Ceppi, S., Bergamelli, L., Cortini, M., Masciarelli, S., Valetti, C., Sitia, R. Sequential steps and checkpoints in the early exocytic compartment during secretory IgM biogenesis (2007) EMBO Journal, 26 (19), pp. 4177-4188.
Mattioli, L., Anelli, T., Fagioli, C., Tacchetti, C., Sitia, R., Valetti, C. ER storage diseases: A role for ERGIC-53 in controlling the formation and shape of Russell bodies (2006) Journal of Cell Science, 119 (12), pp. 2532-2541.
Bertoli, G., Simmen, T., Anelli, T., Molteni, S.N., Fesce, R., Sitia, R. Two conserved cysteine triads in human Ero1α cooperate for efficient disulfide bond formation in the endoplasmic reticulum (2004) Journal of Biological Chemistry, 279 (29), pp. 30047-30052.
Anelli, T., Alessio, M., Bachi, A., Bergamelli, L., Bertoli, G., Camerini, S., Mezghrani, A., Ruffato, E., Simmen, T., Sitia, R. Thiol-mediated protein retention in the endoplasmic reticulum: The role of ERp44 (2003) EMBO Journal, 22 (19), pp. 5015-5022.
Tagliavacca, L., Anelli, T., Fagioli, C., Mezghrani, A., Ruffato, E., Sitia, R. The making of a professional secretory cell: Architectural and functional changes in the ER during B lymphocyte plasma cell differentiation (2003) Biological Chemistry, 384 (9), pp. 1273-1277.
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 (2002) EMBO Journal, 21 (4), pp. 835-844.
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