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First published online 30 May 2006
doi: 10.1242/jcs.02977

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jcs.02977v1 119/12/2532    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mattioli, L. Articles by Valetti, C. Search for Related Content PubMed PubMed Citation Articles by Mattioli, L. Articles by Valetti, C.

ER storage diseases: a role for ERGIC-53 in controlling the formation and shape of Russell bodies

L. Mattioli¹, T. Anelli^2,3, C. Fagioli², C. Tacchetti¹, R. Sitia^2,3,*, and C. Valetti^1,

¹ MicroSCoBiO Research Center and IFOM Center of Cell Oncology and Ultrastructure, Department of Experimental Medicine, University of Genova, Italy
² DiBiT-San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milano, Italy
³ Università Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milano, Italy

^* Author for correspondence (e-mail: r.sitia{at}hsr.it)

Accepted 13 March 2006

Owing to the impossibility of reaching the Golgi for secretion or the cytosol for degradation, mutant Ig-µ chains that lack the first constant domain (µCH1) accumulate as detergent-insoluble aggregates in dilated endoplasmic reticulum cisternae, called Russell bodies. The presence of similar structures hallmarks many ER storage diseases, but their pathogenic role(s) remain obscure. Exploiting inducible cellular systems, we show here that Russell bodies form when the synthesis of µCH1 exceeds the degradation capacity. Condensation occurs in different sub-cellular locations, depending on the interacting molecules present in the host cell: if Ig light chains are co-expressed, detergent-insoluble µCH1-light chain oligomers accumulate in large ribosome-coated structures (rough Russell bodies). In absence of light chains, instead, aggregation occurs in smooth tubular vesicles and is controlled by N-glycan-dependent interactions with ER-Golgi intermediate compartment 53 (ERGIC-53). In cells containing smooth Russell bodies, ERGIC-53 co-localizes with µCH1 aggregates in a Ca²⁺-dependent fashion. Our findings identify a novel ERGIC-53 substrate, and indicate that interactions with light chains or ERGIC-53 seed µCH1 condensation in different stations of the early secretory pathway.

Key words: ER associated degradation, ERGIC-53, ER storage diseases, Protein aggregation, Russell bodies

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