title: Signal-peptide-mediated translocation is regulated by a p97-AIRAPL complex.
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.
authors.affiliation: *Department of Biochemistry, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Glinka
authors.affiliation: *Department of Biochemistry, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Joel
authors.initials: J
authors.lastname: Alter
authors.affiliation: *Department of Biochemistry, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Braunstein
authors.affiliation: *Department of Biochemistry, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Lolita
authors.initials: L
authors.lastname: Tzach
authors.affiliation: †Division of Chemical Biology and BioTechnology, Nanyang Technological University, 60 Nanyang Drive, 639798 Singapore.
authors.forename: Chia
authors.initials: C
authors.lastname: Wei Sheng
authors.affiliation: †Division of Chemical Biology and BioTechnology, Nanyang Technological University, 60 Nanyang Drive, 639798 Singapore.
authors.forename: Susana
authors.initials: S
authors.lastname: Geifman
authors.affiliation: ‡Central Proteomics Facility, Centre for Cellular and Molecular Physiology, Nuffield Department of Clinical Medicine, Oxford University, Roosevelt Drive, Oxford OX3 7BN, U.K.
authors.forename: Mariola J
authors.initials: MJ
authors.lastname: Edelmann
authors.affiliation: ‡Central Proteomics Facility, Centre for Cellular and Molecular Physiology, Nuffield Department of Clinical Medicine, Oxford University, Roosevelt Drive, Oxford OX3 7BN, U.K.
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.affiliation: *Department of Biochemistry, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Stanhill
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D051379:Mice; D011485:Protein Binding / Q000502:physiology; D021382:Protein Sorting Signals / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000074405:Valosin Containing Protein; D016335:Zinc Fingers / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D021382:Protein Sorting Signals; D016601:RNA-Binding Proteins; C544166:ZFAND2B protein, human; C000607774:Zfand2b protein, mouse; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse