Dampening of ISGylation of RIG-I by ADAP regulates type I interferon response of macrophages to RNA virus infection.
Autor: | Yan Wang, Haixia Feng, Xiao Li, Yina Ruan, Yueping Guo, Xinxing Cui, Pengchao Zhang, Yanli Li, Xinning Wang, Xingran Wang, Luxin Wei, Yulan Yi, Lifeng Zhang, Xiaodong Yang, Hebin Liu |
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Jazyk: | angličtina |
Rok vydání: | 2024 |
Předmět: | |
Zdroj: | PLoS Pathogens, Vol 20, Iss 5, p e1012230 (2024) |
Druh dokumentu: | article |
ISSN: | 1553-7366 1553-7374 |
DOI: | 10.1371/journal.ppat.1012230&type=printable |
Popis: | While macrophage is one of the major type I interferon (IFN-I) producers in multiple tissues during viral infections, it also serves as an important target cell for many RNA viruses. However, the regulatory mechanism for the IFN-I response of macrophages to respond to a viral challenge is not fully understood. Here we report ADAP, an immune adaptor protein, is indispensable for the induction of the IFN-I response of macrophages to RNA virus infections via an inhibition of the conjugation of ubiquitin-like ISG15 (ISGylation) to RIG-I. Loss of ADAP increases RNA virus replication in macrophages, accompanied with a decrease in LPS-induced IFN-β and ISG15 mRNA expression and an impairment in the RNA virus-induced phosphorylation of IRF3 and TBK1. Moreover, using Adap-/- mice, we show ADAP deficiency strongly increases the susceptibility of macrophages to RNA-virus infection in vivo. Mechanically, ADAP selectively interacts and functionally cooperates with RIG-I but not MDA5 in the activation of IFN-β transcription. Loss of ADAP results in an enhancement of ISGylation of RIG-I, whereas overexpression of ADAP exhibits the opposite effect in vitro, indicating ADAP is detrimental to the RNA virus-induced ISGylation of RIG-I. Together, our data demonstrate a novel antagonistic activity of ADAP in the cell-intrinsic control of RIG-I ISGylation, which is indispensable for initiating and sustaining the IFN-I response of macrophages to RNA virus infections and replication. |
Databáze: | Directory of Open Access Journals |
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