Notch4 Negatively Regulates the Inflammatory Response to Mycobacterium tuberculosis Infection by Inhibiting TAK1 Activation. (8th December 2017)

• Record Type: Journal Article
• Authors: Zheng, Ruijuan; Liu, Haipeng; Zhou, Yilong; Yan, Dapeng; Chen, Jianxia; Ma, Dapeng; Feng, Yonghong; Qin, Lianhua; Liu, Feng; Huang, Xiaochen; Wang, Jie; Ge, Baoxue
• Is Part Of: Journal of infectious diseases. Volume 218:Number 2(2018)
• Page Start: 312
• Page End: 323
• Publication Date: 2017-12-08
• Subjects: Mycobacterium tuberculosis -- inflammation -- macrophage -- Notch4 -- TAK1; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jix636
• Languages: English
• ISSNs: 0022-1899

Abstract

Abstract : Notch4 is a negative regulator of the host inflammatory response against Mycobacterium tuberculosis infection by inhibiting the activation of TRAF6 and TAK1. Treatment with a Notch inhibitor could serve as a new intervention strategy for tuberculosis. Abstract: Tuberculosis, caused by Mycobacterium tuberculosis infection, remains a global threat to human health, but knowledge of the molecular mechanisms underlying the pathogenesis of tuberculosis is still limited. Although Notch4, a member of the Notch receptor family, is involved in the initiation of mammary tumors, its function in M. tuberculosis infection remains unclear. In this study, we found that Notch4 -deficient mice were more resistant to M. tuberculosis infection, with a much lower bacterial burden and fewer pathological changes in the lungs. Notch4 inhibited M. tuberculosis –induced production of proinflammatory cytokines by interaction with TAK1 and inhibition of its activation. Furthermore, we found that Notch intracellular domain 4 prevented TRAF6 autoubiquitination and suppressed TRAF6-mediated TAK1 polyubiquitination. Finally, Notch inhibitors made mice more resistant to M. tuberculosis infection. These results suggest that Notch4 is a negative regulator of M. tuberculosis –induced inflammatory response, and treatment with a Notch inhibitor could serve as a new therapeutic strategy for tuberculosis.