Slp1-Emp65: A Guardian Factor that Protects Folding Polypeptides from Promiscuous Degradation

Cell. 2017 Oct 5;171(2):346-357.e12. doi: 10.1016/j.cell.2017.08.036. Epub 2017 Sep 14.

Abstract

Newly synthesized proteins engage molecular chaperones that assist folding. Their progress is monitored by quality control systems that target folding errors for degradation. Paradoxically, chaperones that promote folding also direct unfolded polypeptides for degradation. Hence, a mechanism was previously hypothesized that prevents the degradation of actively folding polypeptides. In this study, we show that a conserved endoplasmic reticulum (ER) membrane protein complex, consisting of Slp1 and Emp65 proteins, performs this function in the ER lumen. The complex binds unfolded proteins and protects them from degradation during folding. In its absence, approximately 20%-30% of newly synthesized proteins that could otherwise fold are degraded. Although the Slp1-Emp65 complex hosts a broad range of clients, it is specific for soluble proteins. Taken together, these studies demonstrate the vulnerability of newly translated, actively folding polypeptides and the discovery of a new proteostasis functional class we term "guardian" that protects them from degradation.

Keywords: ER-associated degradation; ERAD; Emp65; Slp1; guardian; protein folding; protein homeostasis; protein quality control; proteostasis.

MeSH terms

  • Animals
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum-Associated Degradation
  • Glycosylation
  • Mice
  • Molecular Chaperones / metabolism
  • Protein Folding*
  • Proteolysis
  • Saccharomyces cerevisiae / cytology
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Vesicular Transport Proteins / chemistry
  • Vesicular Transport Proteins / metabolism*

Substances

  • Emp65 protein, S cerevisiae
  • Molecular Chaperones
  • Saccharomyces cerevisiae Proteins
  • VPS33 protein, S cerevisiae
  • Vesicular Transport Proteins