An HRD/DER-independent ER quality control mechanism involves Rsp5p-dependent ubiquitination and ER-Golgi transport

J Cell Biol. 2002 Jul 8;158(1):91-101. doi: 10.1083/jcb.200201053. Epub 2002 Jul 8.

Abstract

We have identified a new pathway of ER-associated degradation in Saccharomyces cerevisiae that functions separately from the HRD/DER pathway comprised of Hrd1p, Hrd3p, Der1p, and Ubc7p. This pathway, termed Hrd1p independent-proteolysis (HIP), is capable of recognizing and degrading both lumenal (CPY* and PrA*), and integral membrane proteins (Sec61-2p) that misfold in the ER. CPY* overexpression likely saturates the HRD/DER pathway and activates the HIP pathway, so the slowed degradation kinetics of CPY* in a hrd1 Delta strain is restored to a wild-type rate when CPY* is overexpressed. Substrates of HIP require vesicular trafficking between the ER and Golgi apparatus before degradation by the ubiquitin-proteasome system. Ubiquitination of HIP substrates does not involve the HRD/DER pathway ubiquitin ligase Hrd1p, but instead uses another ubiquitin ligase, Rsp5p. HIP is regulated by the unfolded protein response as Ire1p is necessary for the degradation of CPY* when overexpressed, but not when CPY* is expressed at normal levels. Both the HIP and HRD/DER pathways contribute to the degradation of CPY*, and only by eliminating both is CPY* degradation completely blocked.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cytosol / metabolism
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum / metabolism*
  • Endosomal Sorting Complexes Required for Transport
  • Fungal Proteins / metabolism*
  • Golgi Apparatus / metabolism*
  • Kinetics
  • Ligases / metabolism*
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / metabolism*
  • Models, Biological
  • Precipitin Tests
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins*
  • Time Factors
  • Ubiquitin / metabolism*
  • Ubiquitin-Conjugating Enzymes*
  • Ubiquitin-Protein Ligase Complexes*
  • Ubiquitin-Protein Ligases*

Substances

  • DER1 protein, S cerevisiae
  • Endosomal Sorting Complexes Required for Transport
  • Fungal Proteins
  • HRD3 protein, S cerevisiae
  • Membrane Glycoproteins
  • Membrane Proteins
  • Saccharomyces cerevisiae Proteins
  • Ubiquitin
  • UBE2L3 protein, human
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligase Complexes
  • HRD1 protein, S cerevisiae
  • Ubiquitin-Protein Ligases
  • Ligases
  • RSP5 protein, S cerevisiae