Biosensor-integrated transposon mutagenesis reveals as a coordinator of redox homeostasis in .
|Title||Biosensor-integrated transposon mutagenesis reveals as a coordinator of redox homeostasis in .|
|Publication Type||Journal Article|
|Year of Publication||2023|
|Authors||Shee S, Veetil RT, Mohanraj K, Das M, Malhotra N, Bandopadhyay D, Beig H, Birua S, Niphadkar S, Nagarajan SNarayanan, Sinha VKumar, Thakur C, Rajmani RS, Chandra N, Laxman S, Singh M, Samal A, Seshasayee AN, Singh A|
|Date Published||2023 Aug 29|
() is evolutionarily equipped to resist exogenous reactive oxygen species but shows vulnerability to an increase in endogenous ROS (eROS). Since eROS is an unavoidable consequence of aerobic metabolism, understanding how manages eROS levels is essential yet needs to be characterized. By combining the Mrx1-roGFP2 redox biosensor with transposon mutagenesis, we identified 368 genes (redoxosome) responsible for maintaining homeostatic levels of eROS in . Integrating redoxosome with a global network of transcriptional regulators revealed a hypothetical protein (Rv0158) as a critical node managing eROS in Disruption of ( KO) impaired growth, redox balance, respiration, and metabolism of on glucose but not on fatty acids. Importantly, KO exhibited enhanced growth on propionate, and the Rv0158 protein directly binds to methylmalonyl-CoA, a key intermediate in propionate catabolism. Metabolite profiling, ChIP-Seq, and gene-expression analyses indicate that Rv0158 manages metabolic neutralization of propionate toxicity by regulating the methylcitrate cycle. Disruption of enhanced the sensitivity of to oxidative stress, nitric oxide, and anti-TB drugs. Lastly, KO showed poor survival in macrophages and persistence defect in mice. Our results suggest that Rv0158 is a metabolic integrator for carbon metabolism and redox balance in .
|Grant List||IA/S/16/2/502700 / / Wellcome Trust- DBT India Alliance / |
BT/PR13522/COE/34/27/2015 / / DBT /
Graduate Student Fellowship / / Indian Institute of Science /
grant 22-0905-0006-05-987 436 / / DBT-IISc Partnership Program /