Spata2L Suppresses TLR4 Signaling by Promoting CYLD-Mediated Deubiquitination of TRAF6 and TAK1.
Biochemistry (Mosc)
; 87(9): 957-964, 2022 Sep.
Article
em En
| MEDLINE
| ID: mdl-36180997
ABSTRACT
Toll-like receptor 4 (TLR4) is a key pattern recognition receptor that can be activated by bacterial lipopolysaccharide to elicit inflammatory response. Proper activation of TLR4 is critical for the host defense against microbial infections. Since overactivation of TLR4 causes deleterious effects and inflammatory diseases, its activation needs to be tightly controlled by negative regulatory mechanisms, among which the most pivotal could be deubiquitination of key signaling molecules mediated by deubiquitinating enzymes (DUBs). CYLD is a member of the USP family of DUBs that acts as a critical negative regulator of TLR4-depedent inflammatory responses by deconjugating polyubiquitin chains from signaling molecules, such as TRAF6 and TAK1. Dysregulation of CYLD is implicated in inflammatory diseases. However, how the function of CYLD is regulated during inflammatory response remains largely unclear. Recently, we and other authors have shown that Spata2 functions as an important CYLD partner to regulate enzymatic activity of CYLD and substrate binding by this protein. Here, we show that a Spata2-like protein, Spata2L, can also form a complex with CYLD to inhibit the TLR4-dependent inflammatory response. We found that Spata2L constitutively interacts with CYLD and that the deficiency of Spata2L enhances the LPS-induced NF-κB activation and proinflammatory cytokine gene expression. Mechanistically, Spata2L potentiated CYLD-mediated deubiquitination of TRAF6 and TAK1 likely by promoting CYLD enzymatic activity. These findings identify Spata2L as a novel CYLD regulator, provide new insights into regulatory mechanisms underlying CYLD role in TLR4 signaling, and suggest potential targets for modulating TLR4-induced inflammation.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator 6 Associado a Receptor de TNF
/
Receptor 4 Toll-Like
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Biochemistry (Mosc)
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China