Furin-mediated processing in the early secretory pathway: Sequential cleavage and degradation of misfolded insulin receptors

Joseph Bass*, Christopher Turck, Mathias Rouard, Donald F. Steiner

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

Improperly folded membrane proteins are retained in the endoplasmic reticulum and then diverted to a degradative pathway by a network of molecular chaperones and intracellular proteases. Here we report that mutant insulin proreceptors (Pro62) retained in the early secretory pathway undergo proteolytic cleavage at a tetrabasic concensus site for the subtilisin-like protease furin (SPC 1), generating two unstable proteolytic intermediates of 80/120 kDa corresponding to α (135 kDa) and β (90 kDa) subunits. These are degraded more rapidly than the uncleaved proreceptor protein. Site-directed mutagenesis of the normal RKRR processing site prevented cleavage. Use of inhibitors and furin-deficient cell lines confirmed that furin is responsible for proreceptor cleavage; furin overexpression increased the degradation of mutant but not wild-type receptors. Together, these results suggest that processing and degradation occur sequentially for mutant proreceptors.

Original languageEnglish (US)
Pages (from-to)11905-11909
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number22
DOIs
StatePublished - Oct 24 2000

Keywords

  • Biosynthesis
  • Calnexin
  • Calreticulin
  • Degradation
  • Endoplasmic reticulum

ASJC Scopus subject areas

  • General

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