A non-canonical role of the p97 complex in RIG-I antiviral signaling.

Abstract

RIG-I is a well-studied sensor of viral RNA that plays a key role in innate immunity. p97 regulates a variety of cellular events such as protein quality control, membrane reassembly, DNA repair, and the cell cycle. Here, we report a new role for p97 with Npl4-Ufd1 as its cofactor in reducing antiviral innate immune responses by facilitating proteasomal degradation of RIG-I. The p97 complex is able to directly bind both non-ubiquitinated RIG-I and the E3 ligase RNF125, promoting K48-linked ubiquitination of RIG-I at residue K181. Viral infection significantly strengthens the interaction between RIG-I and the p97 complex by a conformational change of RIG-I that exposes the CARDs and through K63-linked ubiquitination of these CARDs. Disruption of the p97 complex enhances RIG-I antiviral signaling. Consistently, administration of compounds targeting p97 ATPase activity was shown to inhibit viral replication and protect mice from vesicular stomatitis virus (VSV) infection. Overall, our study uncovered a previously unrecognized role for the p97 complex in protein ubiquitination and revealed the p97 complex as a potential drug target in antiviral therapy.

• Authors: Qian Hao, Shi Jiao, Zhubing Shi, Chuanchuan Li, Xia Meng, Zhen Zhang, Yanyan Wang, Xiaomin Song, Wenjia Wang, Rongguang Zhang, Yun Zhao, Catherine C L Wong, Zhaocai Zhou
• Journal: The EMBO journal (EMBO J) Vol. 34 Issue 23 Pg. 2903-20 (Dec 02 2015) ISSN: 1460-2075 [Electronic] England
• PMID: 26471729 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors.

Chemical References

• Nuclear Proteins
• PLAAT4 protein, human
• Receptors, Retinoic Acid
• RNF125 protein, mouse
• Ubiquitin-Protein Ligases
• Proteasome Endopeptidase Complex
• Adenosine Triphosphatases
• p97 ATPase

Topics

• Adenosine Triphosphatases (genetics, metabolism)
• Animals
• Cell Line
• HeLa Cells
• Humans
• Mice
• Nuclear Proteins (genetics, metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Binding (genetics, physiology)
• Receptors, Retinoic Acid (genetics, metabolism)
• Signal Transduction
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Ubiquitination (physiology)
• Vesicular Stomatitis (metabolism, prevention & control)
• Virus Replication (physiology)