Journal
EMBO REPORTS
Volume 22, Issue 6, Pages -Publisher
WILEY
DOI: 10.15252/embr.202052175
Keywords
Mycobacterium tuberculosis; NF‐ κ B signaling; protein kinase G; ubiquitin ligase; ubiquitin‐ activating enzyme
Categories
Funding
- National Natural Science Foundation of China [31830003, 81825014, 82022041, 81871616]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB29020000]
- National Key Research and Development Program of China [2019YFA0802100, 2017YFA0505900, 2017YFD0500300]
- National Science and Technology Major Project [2018ZX10101004]
- Youth Innovation Promotion Association CAS [Y82R011CX3]
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The study reveals that PknG acts as both a ubiquitin-activating enzyme and ligase, promoting the degradation of key components of the immune system and inhibiting NF-kappa B signaling, providing a potential target for tuberculosis treatment.
Upon Mycobacterium tuberculosis (Mtb) infection, protein kinase G (PknG), a eukaryotic-type serine-threonine protein kinase (STPK), is secreted into host macrophages to promote intracellular survival of the pathogen. However, the mechanisms underlying this PknG-host interaction remain unclear. Here, we demonstrate that PknG serves both as a ubiquitin-activating enzyme (E1) and a ubiquitin ligase (E3) to trigger the ubiquitination and degradation of tumor necrosis factor receptor-associated factor 2 (TRAF2) and TGF-beta-activated kinase 1 (TAK1), thereby inhibiting the activation of NF-kappa B signaling and host innate responses. PknG promotes the attachment of ubiquitin (Ub) to the ubiquitin-conjugating enzyme (E2) UbcH7 via an isopeptide bond (UbcH7 K82-Ub), rather than the usual C86-Ub thiol-ester bond. PknG induces the discharge of Ub from UbcH7 by acting as an isopeptidase, before attaching Ub to its substrates. These results demonstrate that PknG acts as an unusual ubiquitinating enzyme to remove key components of the innate immunity system, thus providing a potential target for tuberculosis treatment.
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