Progressive quality control of secretory proteins in the early secretory compartment by ERp44

Sara Sannino, Tiziana Anelli, Margherita Cortini, Shoji Masui, Massimo Degano, Claudio Fagioli, Kenji Inaba, Roberto Sitia

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

ERp44 is a pH-regulated chaperone of the secretory pathway. In the acidic milieu of the Golgi, its C-terminal tail changes conformation, simultaneously exposing the substrate-binding site for cargo capture and the RDEL motif for ER retrieval through interactions with cognate receptors. Protonation of cysteine 29 in the active site allows tail movements in vitro and in vivo. Here, we show that conserved histidine residues in the C-terminal tail also regulate ERp44 in vivo. Mutants lacking these histidine residues retain substrates more efficiently. Surprisingly, they are also Oglycosylated and partially secreted. Co-expression of client proteins prevents secretion of the histidine mutants, forcing tail opening and RDEL accessibility. Client-induced RDEL exposure allows retrieval of proteins from distinct stations along the secretory pathway, as indicated by the changes in O-glycosylation patterns upon overexpression of different partners. The ensuing gradients might help to optimize folding and assembly of different cargoes. Endogenous ERp44 is O-glycosylated and secreted by human primary endometrial cells, suggesting possible pathophysiological roles of these processes.

Original languageEnglish
Pages (from-to)4260-4269
Number of pages10
JournalJournal of cell science
Volume127
Issue number19
DOIs
Publication statusPublished - 2014 Jan 1

Keywords

  • ERp44
  • Endoplasmic reticulum
  • Golgi
  • O-glycosylation
  • Protein quality control
  • Protein secretion

ASJC Scopus subject areas

  • Cell Biology

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    Sannino, S., Anelli, T., Cortini, M., Masui, S., Degano, M., Fagioli, C., Inaba, K., & Sitia, R. (2014). Progressive quality control of secretory proteins in the early secretory compartment by ERp44. Journal of cell science, 127(19), 4260-4269. https://doi.org/10.1242/jcs.153239