Autoadaptive ER-associated degradation defines a preemptive unfolded protein response pathway.
Folding-defective proteins must be cleared efficiently from the endoplasmic reticulum (ER) to prevent perturbation of the folding environment and to maintain cellular proteostasis. Misfolded proteins engage dislocation machineries (dislocons) built around E3 ubiquitin ligases that promote their transport across the ER membrane, their polyubiquitylation, and their proteasomal degradation. Here, we report on the intrinsic instability of the HRD1 dislocon and the constitutive, rapid turnover of the scaffold protein HERP. We show that HRD1 dislocon integrity relies on the presence of HRD1 clients that interrupt, in a dose-dependent manner, the UBC6e/RNF5/p97/proteasome-controlled relay that controls HERP turnover. We propose that ER-associated degradation (ERAD) deploys autoadaptive regulatory pathways, collectively defined as ERAD tuning, to rapidly adapt degradation activity to misfolded protein load and to preempt the unfolded protein response (UPR) activation.
Institute for Research in Biomedicine, Protein Folding and Quality Control, 6500 Bellinzona, Switzerland.
Riccardo
R
Bernasconi
Institute for Research in Biomedicine, Protein Folding and Quality Control, 6500 Bellinzona, Switzerland.
Carmela
C
Galli
Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Osaka 565-8565, Japan.
Koichi
K
Kokame
Institute for Research in Biomedicine, Protein Folding and Quality Control, 6500 Bellinzona, Switzerland; Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, 1015 Lausanne, Switzerland. Electronic address: maurizio.molinari@irb.usi.ch.
Maurizio
M
Molinari
D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D014158:Transcription, Genetic; D014162:Transfection; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response
D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; C485932:HERPUD1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C101338:PSMD2 protein, human; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C491497:UFD1 protein, human; C111501:RNF5 protein, human; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease