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Mol Cell Biol. 2018 Jun 14;38(13). pii: e00154-18. doi: 10.1128/MCB.00154-18. Print 2018 Jul 1.

The VCP-UBXN1 Complex Mediates Triage of Ubiquitylated Cytosolic Proteins Bound to the BAG6 Complex.

Author information

1
Department of Developmental Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA.
2
Department of Developmental Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA malavika.raman@tufts.edu.

Abstract

A balance between protein synthesis and degradation is necessary to maintain cellular homeostasis. Failure to triage aberrant proteins may result in their accumulation and aggregation in the cytosol. The valosin-containing protein (VCP)-BCL2-associated athanogene 6 (BAG6) complex facilitates a wide variety of ubiquitin-mediated quality control events at the endoplasmic reticulum (ER), both prior to ER translocation and during ER-associated degradation (ERAD). However, how ubiquitylated clients associated with BAG6 are recognized by VCP for proteasomal degradation is presently unknown. We have identified UBXN1 as the VCP adaptor in BAG6-dependent processes occurring prior to ER insertion but not during ERAD. The loss of VCP-UBXN1 results in the inappropriate stabilization of ubiquitylated BAG6 clients and their accumulation in insoluble aggregates and sensitizes cells to proteotoxic stress. Our results identify how VCP is specifically targeted to ubiquitylated substrates in the BAG6 triage pathway and suggest that the degradation of ubiquitylated clients by the proteasome is reliant on the association of UBXN1 with ubiquitylated substrates and the catalytic activity of VCP.

KEYWORDS:

VCP; proteasome; protein quality control; ubiquitin

PMID:
29685906
PMCID:
PMC6002697
DOI:
10.1128/MCB.00154-18
[Indexed for MEDLINE]
Free PMC Article

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