BORC complex specific components and Kinesin-1 mediate autophagy evasion by the autophagy-resistant Mycobacterium tuberculosis Beijing strain

Abstract

Autophagy induction by starvation has been shown to enhance lysosomal delivery to mycobacterial phagosomes, resulting in the restriction of the Mycobacterium tuberculosis reference strain H37Rv. In contrast to H37Rv, our previous study showed that strains belonging to the notorious M. tuberculosis Beijing genotype could evade autophagic elimination. Our recent RNA-Seq analysis also discovered that the autophagy-resistant M. tuberculosis Beijing strain (BJN) evaded autophagic control by upregulating the expression of Kxd1, a BORC complex component, and Plekhm2, both of which function in lysosome positioning towards the cell periphery in host macrophages, thereby suppressing enhanced lysosomal delivery to its phagosome and sparing the BJN from elimination as a result. In this work, we further characterised the other specific components of the BORC complex, BORC5-8, and Kinesin proteins in autophagy resistance by the BJN. Depletion of BORCS5-8 and Kinesin-1, but not Kinesin-3, reverted autophagy avoidance by the BJN, resulting in increased lysosomal delivery to the BJN phagosomes. In addition, the augmented lysosome relocation towards the perinuclear region could now be observed in the BJN-infected host cells depleted in BORCS5-8 and Kinesin-1 expressions. Taken together, the data uncovered new roles for BORCS5-8 and Kinesin-1 in autophagy evasion by the BJN.

Host‐pathogen dialogues in different cell death modes during Mycobacterium tuberculosis infection

“…As research has advanced, additional factors promoting immune escape have been discovered. For instance, the Mtb Beijing strain (BJN), known for its resistance to autophagy, up‐regulates the components of the BORC complex (Kxd1, Plekhm2, and Kinesin‐1) to move lysosomes toward the cell periphery 84 . Moreover, the upregulation of KatG inhibits autophagic clearance by blocking autophagy‐lysosome fusion and inhibiting ROS release 85 .…”