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- Title
The E3 ligase HERC5 promotes antimycobacterial responses in macrophages by ISGylating the phosphatase PTEN.
- Authors
Du, Xialin; Sheng, Junli; Chen, Yitian; He, Shitong; Yang, Yalong; Huang, Yulan; Fu, Yuling; Lie, Linmiao; Han, Zhenyu; Zhu, Bo; Liu, Honglin; Wen, Qian; Zhou, Xinying; Zhou, Chaoying; Hu, Shengfeng; Ma, Li
- Abstract
Innate immune signaling in macrophages during viral infection is regulated by ISGylation, the covalent attachment of the ubiquitin-like protein interferon-stimulated gene 15 (ISG15) to protein targets. Here, we explored the role of ISGylation in the macrophage response to infection with Mycobacterium tuberculosis. In human and mouse macrophages, the E3 ubiquitin ligases HERC5 and mHERC6, respectively, mediated the ISGylation of the phosphatase PTEN, which promoted its degradation. The decreased abundance of PTEN led to an increase in the activity of the PI3K-AKT signaling pathway, which stimulated the synthesis of proinflammatory cytokines. Bacterial growth was increased in culture and in vivo when human or mouse macrophages were deficient in the major E3 ISG15 ligase. The findings expand the role of ISGylation in macrophages to antibacterial immunity and suggest that HERC5 signaling may be a candidate target for adjunct host-directed therapy in patients with tuberculosis. Editor's summary: The antimicrobial response in macrophages is regulated in part by a protein modification called ISGylation. Du et al. found that ISGylation mediated by the protein HERC5 (or the functional equivalent in mice, HERC6) enabled macrophages to respond to infection with the bacterium that causes tuberculosis. HERC5- or HERC6-mediated ISGylation of the phosphatase PTEN induced its degradation, thus alleviating its suppression of the PI3K-AKT signaling pathway and promoting the production of cytokines that facilitated clearance of the bacteria. The findings reveal a host-response mechanism against tuberculosis that might inform the development of improved treatments for patients. —Leslie K. Ferrarelli
- Subjects
MACROPHAGES; MYCOBACTERIUM tuberculosis; MYCOBACTERIAL diseases; UBIQUITIN ligases; VIRUS diseases; BACTERIAL growth
- Publication
Science Signaling, 2023, Vol 16, Issue 788, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.abm1756