USP1-UAF1 deubiquitinase complex stabilizes TBK1 and enhances antiviral responses.

Abstract

Optimal activation of TANK-binding kinase 1 (TBK1) is crucial for initiation of innate antiviral immunity and maintenance of immune homeostasis. Although several E3 ubiquitin ligases have been reported to regulate TBK1 activation by mediating its polyubiquitination, the functions of deubiquitinase on TBK1 activity remain largely unclear. Here, we identified a deubiquitinase complex, which is formed by ubiquitin specific peptidase 1 (USP1) and USP1-associated factor 1 (UAF1), as a viral infection-induced physiological enhancer of TBK1 expression. USP1-UAF1 complex enhanced TLR3/4 and RIG-I-induced IFN regulatory factor 3 (IRF3) activation and subsequent IFN-β secretion. Mechanistically, USP1 and UAF1 bound to TBK1, removed its K48-linked polyubiquitination, and then reversed the degradation process of TBK1. Furthermore, we found that ML323, a specific USP1-UAF1 inhibitor, attenuated IFN-β expression and enhanced viral replication both in vitro and in vivo. Therefore, our results outline a novel mechanism for the control of TBK1 activity and suggest USP1-UAF1 complex as a potential target for the prevention of viral diseases.

• Authors: Zhongxia Yu, Hui Song, Mutian Jia, Jintao Zhang, Wenwen Wang, Qi Li, Lining Zhang, Wei Zhao
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 214 Issue 12 Pg. 3553-3563 (Dec 04 2017) ISSN: 1540-9538 [Electronic] United States
• PMID: 29138248 (Publication Type: Journal Article)
• Copyright: © 2017 Yu et al.

Chemical References

• Antiviral Agents
• Enzyme Inhibitors
• Interferon Regulatory Factor-3
• Nuclear Proteins
• USP1 associated factor 1, human
• Interferon-beta
• Protein Serine-Threonine Kinases
• TBK1 protein, human
• USP1 protein, human
• Ubiquitin-Specific Proteases
• Lysine

Topics

• Animals
• Antiviral Agents (metabolism)
• Enzyme Inhibitors (pharmacology)
• Enzyme Stability (drug effects)
• Female
• HEK293 Cells
• Humans
• Interferon Regulatory Factor-3 (metabolism)
• Interferon-beta (metabolism)
• Lysine (metabolism)
• Mice
• Mice, Inbred C57BL
• Nuclear Proteins (metabolism)
• Protein Binding (drug effects)
• Protein Serine-Threonine Kinases (metabolism)
• RAW 264.7 Cells
• Ubiquitin-Specific Proteases (metabolism)
• Ubiquitination (drug effects)
• Vesiculovirus (physiology)
• Virus Replication (drug effects)