Dampening of ISGylation of RIG-I by ADAP regulates type I interferon response of macrophages to RNA virus infection.
PLoS Pathog
; 20(5): e1012230, 2024 May.
Article
en En
| MEDLINE
| ID: mdl-38776321
ABSTRACT
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-ß 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-ß 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Infecciones por Virus ARN
/
Ubiquitinas
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Interferón Tipo I
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Ratones Noqueados
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Proteínas Adaptadoras Transductoras de Señales
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Proteína 58 DEAD Box
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Macrófagos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
PLoS Pathog
Año:
2024
Tipo del documento:
Article
País de afiliación:
China