Proteasomal degradation of preemptive quality control (pQC) substrates is mediated by an AIRAPL-p97 complex

Ilana Braunstein, Lolita Zach, Susanne Allan, Kai Uwe Kalies, Ariel Stanhill

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)3719-3727
Number of pages9
JournalMolecular Biology of the Cell
Issue number21
StatePublished - 1 Nov 2015
Externally publishedYes

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Publisher Copyright:
© 2015 Braunstein et al.


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