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Published on: April 18, 2016
Proteasomal degradation of preemptive quality control (pQC) substrates is mediated by an AIRAPL-p97 complex
Ilana Braunstein1, Lolita Zach1, Susanne Allan2
1Department of Biochemistry, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa 31096, Israel.
Abstract:
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.
Insights
Misfolded proteins are degraded by the ubiquitin-proteasome system (UPS). A p97-AIRAPL complex aids this preemptive quality control (pQC) pathway, ensuring efficient degradation of mislocalized proteins.
Area of Science:
- Cell Biology
- Protein Folding
- Molecular Mechanisms
Background:
- Secreted proteins fold in the ER lumen, requiring proper translocation.
- Misfolded proteins lacking translocation are toxic and targeted for degradation.
- The preemptive quality control (pQC) pathway degrades mislocalized proteins via the ubiquitin-proteasome system (UPS).
Purpose of the Study:
- To identify components involved in the pQC pathway.
- To elucidate the mechanism of pQC substrate processing by the UPS.
- To investigate the role of p97 in pQC.
Main Methods:
- Inhibition of protein translocation.
- Analysis of protein ubiquitination and degradation.
- Biochemical assays to study protein complex formation.
Main Results:
- A p97-AIRAPL complex directly binds polyubiquitinated pQC substrates.
- This complex regulates the efficient processing of pQC substrates by the UPS.
- p97 is crucial for pQC processing of preproinsulin with signal sequence mutations.
Conclusions:
- The p97-AIRAPL complex is a key regulator of the pQC pathway.
- p97 facilitates the UPS-mediated degradation of mislocalized proteins.
- Understanding p97's role in pQC offers insights into protein homeostasis and disease.
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