An HRD/DER-independent ER quality control mechanism involves Rsp5p-dependent ubiquitination and ER-Golgi transport.
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.
Haynes
Cole M
CM
University of Missouri-Kansas City, Division of Cell Biology and Biophysics, School of Biological Sciences, Kansas City, MO 64110, USA.
Caldwell
Sabrina
S
Cooper
Antony A
AA
D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport; D005656:Fungal Proteins / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D007700:Kinetics; D008025:Ligases / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D011233:Precipitin Tests; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases
C098515:DER1 protein, S cerevisiae; D056827:Endosomal Sorting Complexes Required for Transport; D005656:Fungal Proteins; C104622:HRD3 protein, S cerevisiae; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; C079437:UBE2L3 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes; C104621:HRD1 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases; D008025:Ligases; C469287:RSP5 protein, S cerevisiae