Quality control of ER synthesized proteins: An exposed thiol group as a three-way switch mediating assembly, retention and degradation

Anna M. Fra, Claudio Fagioli, Dario Finazzi, Roberto Sitia, Cristina M. Alberini

Research output: Contribution to journalArticlepeer-review

Abstract

Plasma cells secrete IgM only in the polymeric form: the C-terminal cysteine of the μ heavy chain (Cys575) is responsible for both intracellular retention and assembly of IgM subunits. Polymerization is not quantitative, and part of IgM is degraded intracellularly. Neither chloroquine nor brefeldin A (BFA) inhibits degradation, suggesting that this process occurs in a pre-Golgi compartment. Degradation of IgM assembly intermediates requires Cys575: the monomeric IgMala575 mutant is stable also when endoplasmic reticulum (ER) to Golgi transport is blocked by BFA. Addition of the 20 C-terminal residues of μ to the lysosomal protease cathepsin D is sufficient to induce pre-Golgi retention and degradation of the chimeric protein: the small amounts of molecules which exit from the ER are mostly covalent dimers. By contrast, when retained by the KDEL sequence, cathepsin D is stable in the ER, indicating that retention is not sufficient to cause degradation. Replacing the C-terminal cysteine with serine restores transport through the Golgi. As all chimeric cathepsin D constructs display comparable protease activity in vitro, their different fates are not determined by gross alterations in folding. Thus, also out of its normal context, the μ chain Cys575 plays a crucial role in quality control, mediating assembly, retention and degradation.

Original languageEnglish (US)
Pages (from-to)4755-4761
Number of pages7
JournalEMBO Journal
Volume12
Issue number12
DOIs
StatePublished - 1993

Keywords

  • Cathepsin D
  • Degradation
  • Endoplasmic reticulum
  • Immunoglobulin
  • Secretion

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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