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To subvert host defenses,  Mycobacterium tuberculosis (Mtb)  avoids being delivered to degradative phagolysosomes in macrophages by arresting the normal host process of phagosome maturation. Phagosome maturation arrest by  Mtb  involves multiple effectors and much remains unknown about this important aspect of  Mtb  pathogenesis. The SecA2 dependent protein export system is required for phagosome maturation arrest and consequently growth of  Mtb  in macrophages. To better understand the role of the SecA2 pathway in phagosome maturation arrest, we identified two effectors exported by SecA2 that contribute to this process: the phosphatase SapM and the kinase PknG. Then, utilizing the  secA2  mutant of  Mtb  as a platform to study effector functions, we identified specific steps in phagosome maturation inhibited by SapM and/or PknG. By identifying a histidine residue that is essential for SapM phosphatase activity, we confirmed for the first time that the phosphatase activity of SapM is required for its effects on phagosome maturation in macrophages. We further demonstrated that SecA2 export of SapM and PknG contributes to the ability of  Mtb  to replicate in macrophages. Finally, we extended our understanding of the SecA2 pathway, SapM, and PknG by revealing that their contribution goes beyond preventing  Mtb  delivery to mature phagolysosomes and includes inhibiting  Mtb  delivery to autophagolysosomes. Together, our results revealed SapM and PknG to be two effectors exported by the SecA2 pathway of  Mtb  with distinct as well as cumulative effects on phagosome and autophagosome maturation. Our results further reveal that  Mtb  must have additional mechanisms of limiting acidification of the phagosome, beyond inhibiting recruitment of the V-ATPase proton pump to the phagosome, and they indicate differences between effects of  Mtb  on phagosome and autophagosome maturation.

The SecA2 pathway of Mycobacterium tuberculosis exports effectors that work in concert to arrest phagosome and autophagosome maturation