Tuberculosis (TB) is a chronic and deadly infectious disease caused by M. tuberculosis (Mtb), an intracellular pathogen that employs multiple effector proteins to manipulate host immune response. Mtb genome encodes for eleven eukaryotic-like serine-threonine protein kinases (STPKs), among which protein kinase G (PknG) is secreted into host cells and is essential for TB pathogenicity and pathogen intracellular survival during Mtb infection.

Dr. LIU Cuihua's group at the Institute of Microbiology of the Chinese Academy of Sciences has been investigating the molecular mechanisms underlying Mtb-host interactions, and has demonstrated that PknG acts as an unusual ubiquitinating enzyme to promote the polyubiquitination and proteasomal degradation of host substrates via a novel two-step cascade, leading to host innate immune suppression.

In a study published online in Autophagy, Dr. LIU's group revealed another important novel mechanism by which Mtb PknG interferes with the host innate immunity.

Basically, PknG targets different stages of the autophagy flux, including autophagy induction stage and autophagosome maturation stage, through distinct regions or its kinase activity, leading to an overall effect of blocked host autophagy flux and enhanced pathogen intracellular survival.

On the one hand, Mtb PknG suppresses the activation of AKT by exploiting its C-terminal region to competitively interact with the pleckstrin homology (PH) domain of AKT, promoting autophagy induction.

On the other hand, PknG binds to RAB14 through its TPR domain, and phosphorylates AS160 to suppress its GTPase-activating protein (GAP) activity towards RAB14 in a kinase activity-dependent manner, keeping RAB14 in a RAB14-GTP state to prevent the maturation of Mtb-containing vesicles, and promoting mycobacterial intracellular survival.

This study reveals the whole picture of the PknG-mediated autophagy flux regulation during Mtb infection, providing potential TB treatment strategies through promoting PknG-AKT interaction to induce the autophagy while targeting the kinase activity of PknG and the PknG-RAB14 interacting interface to release the autophagy flux blockade effect.