Biochemical Journal

Research article

Signal-peptide-mediated translocation is regulated by a p97–AIRAPL complex

Tal Glinka, Joel Alter, Ilana Braunstein, Lolita Tzach, Chia Wei Sheng, Susana Geifman, Mariola J. Edelmann, Benedikt M. Kessler, Ariel Stanhill

Abstract

Protein homoeostasis is a fundamental requirement for all living cells in order to survive in a dynamic surrounding. Proper levels of AIRAPL (arsenite-inducible RNA-associated protein-like protein) (ZFAND2B) are required in order to maintain cellular folding capacity in metazoans, and functional impairment of AIRAPL results in acceleration of aging and protein aggregation. However, the cellular roles of AIRAPL in this process are not known. In the present paper, we report that AIRAPL binds and forms a complex with p97 [VCP (valosin-containing protein)/Cdc48], Ubxd8 (ubiquitin regulatory X domain 8), Npl4–Ufd1, Derlin-1 and Bag6 on the ER (endoplasmic reticulum) membrane. In spite of the fact that AIRAPL complex partners are involved in the ERAD (ER-associated degradation) process, AIRAPL knockdown does not show any impairment in ERAD substrate degradation. However, translocation into the ER of a subset of ERAD- and non-ERAD-secreted proteins are regulated by AIRAPL. The ability to regulate translocation by the p97–AIRAPL complex is entirely dependent on the proteins’ signal peptide. Our results demonstrate a p97 complex regulating translocation into the ER in a signal-peptide-dependent manner.

  • arsenite-inducible RNA-associated protein-like protein (AIRAPL)
  • endoplasmic reticulum translocation
  • p97
  • quality control
  • signal peptide

Abbreviations: AAA, ATPase associated with various cellular activities; AIRAP, arsenite-inducible RNA-associated protein; AIRAPL, AIRAP-like protein; ApoB100, apolipoprotein B100; CID, collision-induced dissociation; ER, endoplasmic reticulum; ERAD, ER-associated degradation; HA, haemagglutinin; NTD, N-terminal domain; SEAP, secreted embryonic alkaline phosphatase; SPR, surface plasmon resonance; TCRα, T-cell receptor α; UBD, ubiquitin-binding domain; Ubl, ubiquitin-like; Ubxd8, ubiquitin regulatory X domain 8; UIM, ubiquitin-interacting motif; UPS, ubiquitin–proteasome system; VCAM-1, vascular cell adhesion molecule 1; VCP, valosin-containing protein; VIM, VCP-interacting motif

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