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Protein Manipulates Host Autophagy Process to Promote M. tuberculosis Survival

Scientists from the Institute of Microbiology of the Chinese Academy of Sciences have uncovered the dual-functionality of M. tuberculosis protein kinase G, providing a potential target for tuberculosis treatment.

According to the World Health Organization, about 10 million people in the world fell ill with tuberculosis (TB) in 2019. TB is a chronic and deadly infectious disease caused by rod-shaped bacteria called Mycobacterium tuberculosis (Mtb). This pesky pathogen engages many proteins that helps it manipulate the host immune response, contributing to its success as one of the leading causes of death in the world.

Previously, Dr Liu Cuihua’s group at the Institute of Microbiology of the Chinese Academy of Sciences demonstrated that a particular protein called protein kinase G promotes protein degradation of host substrates by acting as an unusual ubiquitinating enzyme, that is, marking other proteins with a smaller protein that flags it up for destruction. By destroying the host proteins, bacterial protein kinase G can suppress the host innate immune response, thereby causing disease and survival of Mtb during bacterial infection.

Building on their investigation into Mtb-host interactions, Dr Liu’s group revealed another important mechanism by which Mtb protein kinase G interferes with the host innate immunity.

They found that protein kinase G disrupts different stages of the autophagy flux, which refers to the whole process of autophagy from formation to breakdown and release of macromolecules back into the cytosol. Through its distinct regions or kinase activity, protein kinase G can block the process of autophagy (or the breakdown of cellular proteins and organelles) and enhance the survival of the Mtb bacteria.

By exploiting its C-terminal region to interact with a domain of human AKT protein, the bacterial protein kinase G promotes the initiation of autophagy. However, protein kinase G also binds to another protein RAB14 through a different domain and phosphorylates a substrate AS160 to suppress GTPase-activating protein (GAP) activity. Together, this prevents the maturation of Mtb-containing vesicles, thereby further promoting the survival of the tuberculosis bacteria.

Dr Liu’s work reveals a dual-functional bacterial protein that tightly regulates the host autophagy process to improve bacterial survival. From this, we can derive potential treatment strategies for TB by looking at promoting protein kinase G interaction with AKT to induce autophagy while targeting the kinase activity with AS160 and GAP to release the blockade effect. [APBN]

Source: Ge, et al. (2021). M. tuberculosis PknG manipulates host autophagy flux to promote pathogen intracellular survival. Autophagy.