Mtb PknG hijacks the host linear ubiquitin chain meeting advanced to evade NLRP3 inflammasome-mediated cytosolic immune surveillance. Credit score: Liu Cuihua’s group
A analysis staff has uncovered a brand new mechanism that permits Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis (TB), to evade host immune defenses.
The research, revealed in Cell Studies, reveals how Mtb hijacks the host’s linear ubiquitin equipment to drive inflammasome sensor NLRP3 degradation, thereby counteracting host intracellular immune surveillance.
Mtb continues to pose a menace to sufferers because of the emergence and unfold of antimicrobial resistance. Host immune cells have cytosolic sensors that detect invading pathogens and provoke anti-infectious responses. Nevertheless, how pathogens resembling Mtb undermine host intracellular surveillance to trigger persistent an infection shouldn’t be absolutely understood.
On this research, the researchers, led by Prof. Liu Cuihua from the Institute of Microbiology of the Chinese language Academy of Sciences, discovered that PknG, an Mtb-secreted protein kinase, disrupts NLRP3-mediated immune responses by interfering with the linear ubiquitin chain meeting advanced (LUBAC).
Mechanistically, PknG phosphorylates the HOIL-1L subunit of LUBAC, stopping HOIL-1L from collaborating in LUBAC formation. This disruption impairs the LUBAC-dependent linear ubiquitination of the inflammasome adaptor ASC, finally inhibiting NLRP3 inflammasome meeting.
Moreover, PknG-mediated phosphorylation concurrently prompts HOIL-1L’s intrinsic E3 ubiquitin ligase exercise, enabling HOIL-1L to mediate K48-linked ubiquitination and subsequent degradation of NLRP3.
To sum up, by means of this dual-regulation mechanism that achieves the “one-stone-two-birds” impact as talked about above, PknG can assist promote the escape of Mtb from NLRP3-mediated cytoplasmic immune surveillance, thereby additional facilitating the intracellular survival and an infection of the pathogen.
This research reveals that Mtb exploits the phosphorylation-dependent dynamics of the host linear ubiquitin equipment by means of the PknG/HOIL-1L interplay. This interplay kinds an inter-species enzymatic cascade that drives inflammasome sensor degradation, permitting Mtb to counteract NLRP3-dependent immune surveillance.
These findings additionally present a possible technique for anti-TB remedy and the optimization of the Bacille Calmette-Guérin (BCG) vaccine by concentrating on the PknG/HOIL-1L interface.
Extra info:
Yang Yu et al, Pathogenic phosphorylation of linear ubiquitin equipment causes inflammasome sensor degradation, Cell Studies (2025). DOI: 10.1016/j.celrep.2025.116286
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Chinese language Academy of Sciences
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Tuberculosis bacterium disables key immune sensor to evade host defenses, research reveals (2025, September 19)
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