TRIM28 negatively regulates the RLR signaling pathway by targeting MAVS for degradation via K48-linked polyubiquitination.
J Biol Chem
; 299(5): 104660, 2023 05.
Article
en En
| MEDLINE
| ID: mdl-37119745
ABSTRACT
Mitochondrial antiviral signaling (MAVS) protein is a core signaling adapter in the retinoid acid-inducible gene-I-like receptor (RLR) signaling pathway that recruits downstream signaling factors, ultimately leading to the activation of type â
interferons. However, the mechanisms that modulate the RLR signaling pathway by manipulating MAVS are not fully understood. Previous studies suggested that tripartite motif 28 (TRIM28) participates in regulating innate immune signaling pathways by inhibiting the expression of immune-related genes at the transcriptional level. In this study, we characterized TRIM28 as a negative regulator of the RLR signaling pathway in a MAVS-dependent manner. Overexpression of TRIM28 inhibited the MAVS-induced production of type â
interferons and proinflammatory cytokines, while knocking down TRIM28 exerted the opposite effect. Mechanistically, TRIM28 targeted MAVS for proteasome-mediated degradation via K48-linked polyubiquitination. The RING domain of TRIM28, especially the cysteine residues at positions 65 and 68, was critical for the suppressive effect of TRIM28 on MAVS-mediated RLR signaling, while each of the C-terminal domains of TRIM28 contributed to its interaction with MAVS. Further investigation revealed that TRIM28 transferred ubiquitin chains to the K7, K10, K371, K420, and K500 residues of MAVS. Together, our results reveal a previously uncharacterized mechanism involving TRIM28 in fine-tuning innate immune responses and provide new insights into the mechanisms by which MAVS is regulated, which contribute to the understanding of the molecular mechanisms underlying immune homeostasis maintenance.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Interferón Tipo I
/
Proteínas Adaptadoras Transductoras de Señales
/
Proteína 28 que Contiene Motivos Tripartito
Idioma:
En
Revista:
J Biol Chem
Año:
2023
Tipo del documento:
Article
País de afiliación:
China