Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
Intervalo de ano de publicação
1.
Mol Cell ; 82(11): 2032-2049.e7, 2022 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-35460603

RESUMO

Virus infection modulates both host immunity and host genomic stability. Poly(ADP-ribose) polymerase 1 (PARP1) is a key nuclear sensor of DNA damage, which maintains genomic integrity, and the successful application of PARP1 inhibitors for clinical anti-cancer therapy has lasted for decades. However, precisely how PARP1 gains access to cytoplasm and regulates antiviral immunity remains unknown. Here, we report that DNA virus induces a reactive nitrogen species (RNS)-dependent DNA damage and activates DNA-dependent protein kinase (DNA-PK). Activated DNA-PK phosphorylates PARP1 on Thr594, thus facilitating the cytoplasmic translocation of PARP1 to inhibit the antiviral immunity both in vitro and in vivo. Mechanistically, cytoplasmic PARP1 interacts with and directly PARylates cyclic GMP-AMP synthase (cGAS) on Asp191 to inhibit its DNA-binding ability. Together, our findings uncover an essential role of PARP1 in linking virus-induced genome instability with inhibition of host immunity, which is of relevance to cancer, autoinflammation, and other diseases.


Assuntos
Antivirais , Nucleotidiltransferases , Antivirais/farmacologia , Citoplasma/genética , Citoplasma/metabolismo , DNA , Dano ao DNA , Instabilidade Genômica , Humanos , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo
2.
Cell Host Microbe ; 31(11): 1820-1836.e10, 2023 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-37848028

RESUMO

Mycobacterium tuberculosis (Mtb) triggers distinct changes in macrophages, resulting in the formation of lipid droplets that serve as a nutrient source. We discover that Mtb promotes lipid droplets by inhibiting DNA repair responses, resulting in the activation of the type-I IFN pathway and scavenger receptor-A1 (SR-A1)-mediated lipid droplet formation. Bacterial urease C (UreC, Rv1850) inhibits host DNA repair by interacting with RuvB-like protein 2 (RUVBL2) and impeding the formation of the RUVBL1-RUVBL2-RAD51 DNA repair complex. The suppression of this repair pathway increases the abundance of micronuclei that trigger the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway and subsequent interferon-ß (IFN-ß) production. UreC-mediated activation of the IFN-ß pathway upregulates the expression of SR-A1 to form lipid droplets that facilitate Mtb replication. UreC inhibition via a urease inhibitor impaired Mtb growth within macrophages and in vivo. Thus, our findings identify mechanisms by which Mtb triggers a cascade of cellular events that establish a nutrient-rich replicative niche.


Assuntos
Interferon Tipo I , Mycobacterium tuberculosis , Mycobacterium tuberculosis/genética , Urease/metabolismo , Interferon beta/metabolismo , Interferon Tipo I/metabolismo , Macrófagos/metabolismo , Nucleotidiltransferases/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA