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bioRxiv · 10.1101/2020.05.04.076976

ESAT-6 of Mycobacterium tuberculosis downregulates cofilin1 and reduces the phagosome acidification in infected macrophages

P P, M.·R J, R.·K C, S.·Mundayoor, S.
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Abstract

Mycobacterium tuberculosis when phagocytosed by macrophages is not cleared completely and many of the bacteria remain in phagosomes indefinitely. In this study we considered abnormal retention of filamentous actin on early phagosomes contributing to defective phagosome acidification. The actin depolymerizing protein cofilin1 was found downregulated in macrophages infected with virulent M. tuberculosis. Also, phosphocofilin1, the inactive form of cofilin1, which leads to retention of filamentous actin, and the total filamentous actin itself were found upregulated in macrophages infected with virulent M. tuberculosis. Over expression of constitutively active cofilin1 in macrophages was found to decrease the level of filamentous actin and increase phagosome acidification when infected with virulent M. tuberculosis. The anticancer drug sorafenib which activates cofilin1 in PI3K dependent manner was also found to decrease the filamentous actin level and increase phagosome acidification. Cofilin1, known to be positively regulated by superoxide was found to be downregulated by ESAT-6 of M. tuberculosis where the latter is known to reduce ROS in macrophages. Ectopic expression of ESAT-6 in macrophages was found to downregulate cofilin1, increase filamentous actin and to transform the macrophages more spindle shaped. ESAT-6 was also found to decrease phagosome acidification in macrophages infected with an avirulent M. tuberculosis strain. Finally, this study proposes a role for the amino acid methionine in resisting ROS by creating M93 mutants of ESAT-6.

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P P, M., R J, R., K C, S., Mundayoor, S.. 2020-05-04. ESAT-6 of Mycobacterium tuberculosis downregulates cofilin1 and reduces the phagosome acidification in infected macrophages. https://doi.org/10.1101/2020.05.04.076976

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