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Pradhan, Gourango and Shrivastva, Rohini and Mukhopadhyay, Sangita (2018) Mycobacterial PknG Targets the Rab7l1 Signaling Pathway To Inhibit Phagosome–Lysosome Fusion. The Journal of Immunology, 201 (5). pp. 1421-1433. ISSN 0022-1767

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Abstract

Phagosome maturation is an important innate defense mechanism of macrophages against bacterial infections. The mycobacterial secretory protein kinase G (PknG), a serine/threonine kinase, is known to block phagosome-lysosome (P-L) fusion, and the kinase activity of PknG appears to be crucial for this. However, the detail mechanisms are not well understood. In the current study, we demonstrate that PknG of Mycobacterium sp interacts with the human Rab GTPase protein, Rab7l1, but not with other Rab proteins as well as factors like Rabaptin, Rabex5, PI3K3, Mon1a, Mon1b, early endosome autoantigen 1, and LAMP2 that are known to play crucial roles in P-L fusion. The Rab7l1 protein is shown to play a role in P-L fusion during mycobacterial infection, and its absence promotes survival of bacilli inside macrophages. PknG was found to be translocated to the Golgi complex where it interacted with GDP-bound Rab7l1 and blocked transition of inactive Rab7l1-GDP to active Rab7l1-GTP, resulting in inhibition of recruitment of Rab7l1-GTP to bacilli-containing phagosomes, and these processes are dependent on the kinase activity of PknG. Localization of Rab7l1-GTP to phagosomes was found to be critical for the subsequent recruitment of other phago-lysosomal markers like early endosome autoantigen 1, Rab7, and LAMP2 during infection. Thus, by interfering with the Rab7l1 signaling process, PknG prevents P-L fusion and favors bacterial survival inside human macrophages. This study highlights a novel role of Rab7l1 in the phagosomal maturation process and hints at unique strategies of mycobacteria used to interfere with Rab7l1 function to favor its survival inside human macrophages.

Item Type: Article
Depositing User: Dr P Divakar
Date Deposited: 27 Jul 2018 05:28
Last Modified: 27 Aug 2018 06:15
URI: http://cdfd.sciencecentral.in/id/eprint/857

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