Proteasomal degradation of preemptive quality control (pQC) substrates is mediated by an AIRAPL-p97 complex.
The initial folding of secreted proteins occurs in the ER lumen, which contains specific chaperones and where posttranslational modifications may occur. Therefore lack of translocation, regardless of entry route or protein identity, is a highly toxic event, as the newly synthesized polypeptide is misfolded and can promiscuously interact with cytosolic factors. Mislocalized proteins bearing a signal sequence that did not successfully translocate through the translocon complex are subjected to a preemptive quality control (pQC) pathway and are degraded by the ubiquitin-proteasome system (UPS). In contrast to UPS-mediated, ER-associated degradation, few components involved in pQC have been identified. Here we demonstrate that on specific translocation inhibition, a p97-AIRAPL complex directly binds and regulates the efficient processing of polyubiquitinated pQC substrates by the UPS. We also demonstrate p97's role in pQC processing of preproinsulin in cases of naturally occurring mutations within the signal sequence of insulin.
Department of Biochemistry, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa 31096, Israel.
Ilana
I
Braunstein
Department of Biochemistry, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa 31096, Israel.
Lolita
L
Zach
Centre for Structural and Cell Biology in Medicine, University of Lübeck, 23538 Lübeck, Germany.
Susanne
S
Allan
Centre for Structural and Cell Biology in Medicine, University of Lübeck, 23538 Lübeck, Germany.
Kai-Uwe
KU
Kalies
Department of Biochemistry, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa 31096, Israel stanhill@tx.technion.ac.il.
Ariel
A
Stanhill
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D021382:Protein Sorting Signals; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination; D028961:beta Karyopherins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C424166:KPNB1 protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D021382:Protein Sorting Signals; D025801:Ubiquitin; C544166:ZFAND2B protein, human; D028961:beta Karyopherins; D046988:Proteasome Endopeptidase Complex