1. Academic Validation
  2. PZR suppresses innate immune response to RNA viral infection by inhibiting MAVS activation in interferon signaling mediated by RIG-I and MDA5

PZR suppresses innate immune response to RNA viral infection by inhibiting MAVS activation in interferon signaling mediated by RIG-I and MDA5

  • Antiviral Res. 2024 Jan 5:105797. doi: 10.1016/j.antiviral.2024.105797.
Rilin Deng 1 Lini Zhang 1 Shengwen Chen 1 Xinran Li 1 Binbin Xue 1 Huiyi Li 1 Yan Xu 1 Renyun Tian 1 Qian Liu 1 Luoling Wang 1 Shun Liu 1 Di Yang 1 Penghui Li 1 Songqing Tanga 1 Haizhen Zhu 2
Affiliations

Affiliations

  • 1 Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, Hunan, China.
  • 2 Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, Hunan, China; Key Laboratory of Tropical Translational Medicine of Ministry of Education, Department of Pathogen Biology and Immunology, Institute of Pathogen Biology and Immunology, School of Basic Medicine and Life Science, Department of Clinical Laboratory of the Second Affiliated Hospital, The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, The Second Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, 571199, Hainan, China. Electronic address: hy0206218@hainmc.edu.cn.
Abstract

RNA viral infections seriously endanger human health. Src homology 2 (SH2) domain-containing protein tyrosine Phosphatase 2 (SHP2) suppresses innate immunity against influenza A virus, and pharmacological inhibition of SHP2 provokes hepatic innate immunity. SHP2 binds and catalyzes tyrosyl dephosphorylation of protein zero-related (PZR), but the regulatory effect of PZR on innate immune response to viral Infection is unclear. In this study, the transcription and protein level of PZR in host cells were found to be decreased with RNA viral Infection, and high level of PZR was uncovered to inhibit IFN signaling mediated by RIG-I and MDA5. Through localizing in mitochondria, PZR targeted and interacted with MAVS (also known as IPS-1/VISA/Cardif), suppressing the aggregation and activation of MAVS. Specifically, Y263 residue in ITIM is critical for PZR to exert immunosuppression under RNA viral Infection. Moreover, the recruited SHP2 by PZR that modified with tyrosine phosphorylation under RNA viral Infection might inhibit phosphorylation activation of MAVS. In conclusion, PZR and SHP2 suppress innate immune response to RNA viral Infection through inhibiting MAVS activation. This study reveals the regulatory mechanism of PZR-SHP2-MAVS signal axis on IFN signaling mediated by RIG-I and MDA5, which may provide new sight for developing Antiviral drugs.

Keywords

Innate immune response; MAVS; PZR; RNA viral infection; SHP2.

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