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Complex of Fas-associated Factor 1 (FAF1) with Valosin-containing Protein (VCP)-Npl4-Ufd1 and Polyubiquitinated Proteins Promotes Endoplasmic Reticulum-associated Degradation (ERAD) *

Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 288, Issue: 10, Page: 6998-7011
2013
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Article Description

Fas-associated factor 1 (FAF1) is a ubiquitin receptor containing multiple ubiquitin-related domains including ubiquitin-associated (UBA), ubiquitin-like (UBL) 1, UBL2, and ubiquitin regulatory X (UBX). We previously showed that N-terminal UBA domain recognizes Lys 48 -ubiquitin linkage to recruit polyubiquitinated proteins and that a C-terminal UBX domain interacts with valosin-containing protein (VCP). This study shows that FAF1 interacts only with VCP complexed with Npl4-Ufd1 heterodimer, a requirement for the recruitment of polyubiquitinated proteins to UBA domain. Intriguingly, VCP association to C-terminal UBX domain regulates ubiquitin binding to N-terminal UBA domain without direct interaction between UBA and UBX domains. These interactions are well characterized by structural and biochemical analysis. VCP-Npl4-Ufd1 complex is known as the machinery required for endoplasmic reticulum-associated degradation. We demonstrate here that FAF1 binds to VCP-Npl4-Ufd1 complex via UBX domain and polyubiquitinated proteins via UBA domain to promote endoplasmic reticulum-associated degradation. Background: FAF1, which has multiple ubiquitin-like domains, interacts with various proteins (VCP, Hsp70, and polyubiquitinated proteins). Results: Association of FAF1 UBX with VCP-Npl4-Ufd1 complex regulates ubiquitin binding to FAF1 UBA domain and promotes CD3δ degradation in ERAD. Conclusion: FAF1 is a ubiquitin receptor that promotes ERAD by delivering polyubiquitinated proteins from UBX domain to UBA domain. Significance: FAF1 plays a role in ERAD by modulating domain-domain interaction.

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