Assembly of the WHIP-TRIM14-PPP6C Mitochondrial Complex Promotes RIG-I-Mediated Antiviral Signaling

Mol Cell. 2017 Oct 19;68(2):293-307.e5. doi: 10.1016/j.molcel.2017.09.035.

Peng Tan ¹, Lian He ², Jun Cui ³, Chen Qian ⁴, Xin Cao ⁴, Meng Lin ⁴, Qingyuan Zhu ⁴, Yinyin Li ¹, Changsheng Xing ⁴, Xiao Yu ⁴, Helen Y Wang ⁵, Rong-Fu Wang ⁶

Affiliations

1 Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.
2 Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA.
3 Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, College of Life Sciences, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510275, China.
4 Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.
5 Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA. Electronic address: ywang4@houstonmethodist.org.
6 Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA. Electronic address: rwang3@houstonmethodist.org.

PMID: 29053956 DOI: 10.1016/j.molcel.2017.09.035

Abstract

Mitochondrial Antiviral signaling platform protein (MAVS) acts as a central hub for RIG-I receptor proximal signal propagation. However, key components in the assembly of the MAVS mitochondrial platform that promote RIG-I mitochondrial localization and optimal activation are still largely undefined. Employing pooled RNAi and yeast two-hybrid screenings, we report that the mitochondrial adaptor protein tripartite motif (TRIM)14 provides a docking platform for the assembly of the mitochondrial signaling complex required for maximal activation of RIG-I-mediated signaling, consisting of WHIP and protein Phosphatase PPP6C. Following viral Infection, the ubiquitin-binding domain in WHIP bridges RIG-I with MAVS by binding to polyUb chains of RIG-I at lysine 164. The ATPase domain in WHIP contributes to stabilization of the RIG-I-dsRNA interaction. Moreover, Phosphatase PPP6C is responsible for RIG-I dephosphorylation. Together, our findings define the WHIP-TRIM14-PPP6C mitochondrial signalosome required for RIG-I-mediated innate Antiviral immunity.

Keywords

ATPase domain; K63 ubiquitination; RIG-I-like receptor signaling; dephosphorylation; mitochondrial signalosome; ubiquitin binding.

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