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A Mycobacterium tuberculosis effector protein attacks host innate immunity by acting as an unusual ubiquitinating enzyme

By Jing Wang, Pupu Ge, Zehui Lei, Lihua Qiang, Qiyao Chai, Yong Zhang, Zhe Lu, Dongdong Zhao, Bingxi Li, Jiaqi Su, Ruchao Peng, Yu Pang, Yi Shi, George Fu Gao, Xiao-Bo Qiu, Cui Hua Liu

Posted 06 Nov 2020
bioRxiv DOI: 10.1101/2020.11.05.370551

Protein kinase G (PknG), a eukaryotic type serine and threonine protein kinase (STPK) in Mycobacterium tuberculosis (Mtb), is secreted into the cytosol of infected macrophages to promote intracellular survival of mycobacteria and has been considered as a promising therapeutic target for tuberculosis (TB) treatment. However, the molecular details of Mtb PknG and host intracellular interactions remain obscure. Here, we demonstrate that PknG serves as both the ubiquitin activating enzyme (E1) and the ubiquitin ligase (E3) to promote ubiquitination and degradation of tumor necrosis factor receptor associated factor 2 (TRAF2) and TGFβ activated kinase 1 (TAK1), and thus inhibits the NFκB mediated host innate immune responses. Surprisingly, PknG promotes the attachment of ubiquitin (Ub) to ubiquitin conjugating enzyme (E2) UbcH7 via an isopeptide bond (UbcH7 K82 Ub), instead of a usual C86 Ub thiolester bond, and then promotes the discharge of Ub from UbcH7 by acting as an isopeptidase before attaching Ub to its substrates TRAF2 and TAK1. These results demonstrate that Mtb PknG promotes ubiquitination of the key components of the host innate immunity by acting as an unusual ubiquitinating enzyme to suppress innate immunity. Our findings provide a potential TB treatment via targeting unconventional ubiquitinating activities of PknG. ### Competing Interest Statement The authors have declared no competing interest.

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