Abstract
The host always employs various ways to defend against viral infection and spread. However, viruses have evolved their own effective strategies, such as inhibition of RNA translation of the antiviral effectors, to destroy the host’s defense barriers. Protein synthesis, commonly controlled by the α-subunit of eukaryotic translation initiation factor 2 (eIF2α), is a basic cellular biological process among all species. In response to viral infection, in addition to inducing the transcription of antiviral cytokines by innate immunity, infected cells also inhibit the RNA translation of antiviral factors by activating the protein kinase R (PKR)-eIF2α signaling pathway. Regulation of innate immunity has been well studied; however, regulation of the PKR-eIF2α signaling pathway remains unclear. In this study, we found that the E3 ligase TRIM21 negatively regulates the PKR-eIF2α signaling pathway. Mechanistically, TRIM21 interacts with the PKR phosphatase PP1α and promotes K6-linked polyubiquitination of PP1α. Ubiquitinated PP1α augments its interaction with PKR, causing PKR dephosphorylation and subsequent translational inhibition release. Furthermore, TRIM21 can constitutively restrict viral infection by reversing PKR-dependent translational inhibition of various previously known and unknown antiviral factors. Our study highlights a previously undiscovered role of TRIM21 in regulating translation, which will provide new insights into the host antiviral response and novel targets for the treatment of translation-associated diseases in the clinic.
Funder
National Natural Science Foundation of China
National Major Science and Technology Projects of China
Postdoctoral Research Foundation of China
Hunan Provincial Innovation Foundation for Postgraduate
Publisher
Public Library of Science (PLoS)
Subject
Virology,Genetics,Molecular Biology,Immunology,Microbiology,Parasitology
Reference48 articles.
1. Role of eIF2alpha Kinases in Translational Control and Adaptation to Cellular Stress.;RC Wek;Cold Spring Harb Perspect Biol.,2018
2. Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathway;Z Talloczy;Proc Natl Acad Sci U S A,2002
3. The integrated stress response;K Pakos-Zebrucka;EMBO Rep,2016
4. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease;GS Hotamisligil;Cell,2010
5. Cellular origins of dsRNA, their recognition and consequences;YG Chen;Nat Rev Mol Cell Biol,2022
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