Protein kinase G confers survival advantage to Mycobacterium tuberculosis during latency-like conditions

Khan, Mehak Zahoor and Bhaskar, Ashima and Upadhyay, Sandeep and Kumari, Pooja and Rajmani, Raju S and Jain, Preeti and Singh, Amit and Kumar, Dhiraj and Bhavesh, Neel Sarovar and Nandicoori, Vinay Kumar (2017) Protein kinase G confers survival advantage to Mycobacterium tuberculosis during latency-like conditions. In: JOURNAL OF BIOLOGICAL CHEMISTRY, 292 (39). pp. 16093-16108.

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Abstract

Protein kinase G (PknG), a thioredoxin-fold-containing eukaryotic-like serine/threonine protein kinase, is a virulence factor in Mycobacterium tuberculosis, required for inhibition of phagolysosomal fusion. Here, we unraveled novel functional facets of PknG during latency-like conditions. We found that PknG mediates persistence under stressful conditions like hypoxia and abets drug tolerance. PknG mutant displayed minimal growth in nutrient-limited conditions, suggesting its role in modulating cellular metabolism. Intracellular metabolic profiling revealed that PknG is necessary for efficient metabolic adaptation during hypoxia. Notably, the PknG mutant exhibited a reductive shift in mycothiol redox potential and compromised stress response. Exposure to antibiotics and hypoxic environment resulted in higher oxidative shift in mycothiol redox potential of PknG mutant compared with the wild type. Persistence during latency-like conditions required kinase activity and thioredoxin motifs of PknG and is mediated through phosphorylation of a central metabolic regulator GarA. Finally, using a guinea pig model of infection, we assessed the in vivo role of PknG in manifestation of disease pathology and established a role for PknG in the formation of stable granuloma, hallmark structures of latent tuberculosis. Taken together, PknG-mediated GarA phosphorylation is important for maintenance of both mycobacterial physiology and redox poise, an axis that is dispensable for survival under normoxic conditions but is critical for non-replicating persistence of mycobacteria. In conclusion, we propose that PknG probably acts as a modulator of latency-associated signals.

Item Type:	Journal Article
Publication:	JOURNAL OF BIOLOGICAL CHEMISTRY
Additional Information:	Copy right for this article belongs to the AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	30 Oct 2017 03:40
Last Modified:	30 Oct 2017 03:40
URI:	http://eprints.iisc.ac.in/id/eprint/58107

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