TB Bacterium Disables Key Immune Sensor to Evade Host Defenses, Study Reveals
23 September 2025
A research team has uncovered a new mechanism that allows Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis (TB), to evade host immune defenses.
The study, published in Cell Reports, shows how Mtb hijacks the host’s linear ubiquitin machinery to drive inflammasome sensor NLRP3 degradation, thereby counteracting host intracellular immune surveillance.
Mtb continues to pose a threat to patients due to the emergence and spread of antimicrobial resistance. Host immune cells have cytosolic sensors that detect invading pathogens and initiate anti-infectious responses. However, how pathogens such as Mtb undermine host intracellular surveillance to cause persistent infection is not fully understood.
In this study, the researchers, led by Prof. Liu Cuihua from the Institute of Microbiology of the Chinese Academy of Sciences, found that PknG, an Mtb-secreted protein kinase, disrupts NLRP3-mediated immune responses by interfering with the linear ubiquitin chain assembly complex (LUBAC).
Mechanistically, PknG phosphorylates the HOIL-1L subunit of LUBAC, preventing HOIL-1L from participating in LUBAC formation. This disruption impairs the LUBAC-dependent linear ubiquitination of the inflammasome adaptor ASC, ultimately inhibiting NLRP3 inflammasome assembly.
Additionally, PknG-mediated phosphorylation concurrently activates HOIL-1L’s intrinsic E3 ubiquitin ligase activity, enabling HOIL-1L to mediate K48-linked ubiquitination and subsequent degradation of NLRP3.
To sum up, through this dual-regulation mechanism that achieves the “one-stone-two-birds” effect as mentioned above, PknG can help promote the escape of Mtb from NLRP3-mediated cytoplasmic immune surveillance, thereby further facilitating the intracellular survival and infection of the pathogen.
This study reveals that Mtb exploits the phosphorylation-dependent dynamics of the host linear ubiquitin machinery through the PknG/HOIL-1L interaction. This interaction forms an inter-species enzymatic cascade that drives inflammasome sensor degradation, allowing Mtb to counteract NLRP3-dependent immune surveillance.
These findings also provide a potential strategy for anti-TB therapy and the optimization of the Bacille Calmette-Guérin (BCG) vaccine by targeting the PknG/HOIL-1L interface.
More information: Yang Yu et al, Pathogenic phosphorylation of linear ubiquitin machinery causes inflammasome sensor degradation, Cell Reports (2025). DOI: 10.1016/j.celrep.2025.116286
Source: Medical Xpress
