The E3 Ubiquitin Ligase HERC5 Promotes Antimycobacterial Immunity in Macrophages Through Regulating ISGylation and Degradation of PTEN

HERC5 (homologous to mouse HERC6) is an E3 enzyme that mediates interferon-stimulated gene 15 (ISG15)-induced ISGylation of protein targets to inhibit protein function, thereby playing a vital role in various physiological functions. However, the direct role of HERC5 in macrophages after M. tuberculosis infection has not yet been studied. In the present study, we showed that HERC5 plays a vital role in promoting the inflammatory immune response. HERC5 deficiency in macrophages enhanced bacterial growth, both in vitro and in vivo. We demonstrated that HERC5 increased pro-inflammatory cytokine production in macrophages by positively regulating the PI3K-AKT signaling pathway. Finally, we found that HERC5 regulated PTEN ISGylation and degradation, thereby promoting activation of the PI3K-AKT signaling pathway. Our findings identified an essential role of HERC5 in the ISGylation of PTEN and contributed to our understanding of its protective effects against M. tuberculosis infection. Therefore, HERC5 is a potential target for therapeutic intervention against tuberculosis. Funding Information: This work was supported National Natural Science Foundation of China (81772150, 81901614, 82072242, 82070906), Guangdong Basic and Applied Basic Research Foundation (2019A1515011103). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: All the mice were maintained under specific pathogen-free conditions with the approval of the Scientific Investigation Board of the Biosafety Management Committee of Southern Medical University