HRD gene dependence of endoplasmic reticulum-associated degradation.
Work from several laboratories has indicated that many different proteins are subject to endoplasmic reticulum (ER) degradation by a common ER-associated machinery. This machinery includes ER membrane proteins Hrd1p/Der3p and Hrd3p and the ER-associated ubiquitin-conjugating enzymes Ubc7p and Ubc6p. The wide variety of substrates for this degradation pathway has led to the reasonable hypothesis that the HRD (Hmg CoA reductase degradation) gene-encoded proteins are generally involved in ER protein degradation in eukaryotes. We have tested this model by directly comparing the HRD dependency of the ER-associated degradation for various ER membrane proteins. Our data indicated that the role of HRD genes in protein degradation, even in this highly defined subset of proteins, can vary from absolute dependence to complete independence. Thus, ER-associated degradation can occur by mechanisms that do not involve Hrd1p or Hrd3p, despite their apparently broad envelope of substrates. These data favor models in which the HRD gene-encoded proteins function as specificity factors, such as ubiquitin ligases, rather than as factors involved in common aspects of ER degradation.
Wilhovsky
S
S
University of California San Diego, Department of Biology, La Jolla, California 92093, USA.
Gardner
R
R
Hampton
R
R
D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D019751:Intramolecular Transferases; D008025:Ligases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D033704:Nucleotide Transport Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D006180:Proton-Translocating ATPases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases; D015003:Yeasts / Q000235:genetics / Q000378:metabolism
C035528:FUR4 protein, S cerevisiae; D005656:Fungal Proteins; C104622:HRD3 protein, S cerevisiae; D006609:High Mobility Group Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D033704:Nucleotide Transport Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D014452:Ubiquitins; C079437:UBE2L3 protein, human; D044763:Ubiquitin-Conjugating Enzymes; C104621:HRD1 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases; D019751:Intramolecular Transferases; C068903:DEG1 protein, S cerevisiae; D008025:Ligases