Host F-Box Protein 22 Enhances the Uptake of Brucella by Macrophages and Drives a Sustained Release of Proinflammatory Cytokines through Degradation of the Anti-Inflammatory Effector Proteins of Brucella.
Infect Immun
; 90(5): e0006022, 2022 05 19.
Article
en En
| MEDLINE
| ID: mdl-35420446
ABSTRACT
Brucella species are intracellular bacterial pathogens, causing the worldwide zoonotic disease brucellosis. Brucella invades professional and nonprofessional phagocytic cells, followed by resisting intracellular killing and establishing a replication permissive niche. Brucella also modulates the innate and adaptive immune responses of the host for its chronic persistence. The complex intracellular cycle of Brucella depends in a major way on multiple host factors, but limited information is available on host and bacterial proteins that play an essential role in the invasion, intracellular replication, and modulation of host immune responses. By employing a small interfering RNA (siRNA) screening, we identified a role for the host protein FBXO22 in the Brucella-macrophage interaction. FBXO22 is the key element in the SCF E3 ubiquitination complex, where it determines the substrate specificity for ubiquitination and degradation of various host proteins. Downregulation of FBXO22 by siRNA or the CRISPR-Cas9 system resulted in diminished uptake of Brucella into macrophages, which was dependent on NF-κB-mediated regulation of phagocytic receptors. FBXO22 expression was upregulated in Brucella-infected macrophages, which resulted in induction of phagocytic receptors and enhanced production of proinflammatory cytokines through NF-κB. Furthermore, we found that FBXO22 recruits the effector proteins of Brucella, including the anti-inflammatory proteins TcpB and OMP25, for degradation through the SCF complex. We did not observe any role for another F-box-containing protein of the SCF complex, ß-TrCP, in the Brucella-macrophage interaction. Our findings unravel novel functions of FBXO22 in host-pathogen interaction and its contribution to pathogenesis of infectious diseases.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Brucella
/
Brucelosis
/
Proteínas F-Box
Límite:
Humans
Idioma:
En
Revista:
Infect Immun
Año:
2022
Tipo del documento:
Article
País de afiliación:
India