Salmonella Typhimurium effector SseI regulates host peroxisomal dynamics to acquire lysosomal cholesterol for better intracellular growth

Raj, D.; Nair, A. V.; Sharma, J.; Prakash, S.; Kaushik, A.; Basu, S.; Sahu, S.; Singh, S.; Bhosale, V.; Chandra, T.; Ghoshal, U. C.; Dasgupta, A.; Siddiqi, M. I.; Gupta, S. K.; Chakravortty, D.; Ammanathan, V.; LAHIRI, A.

doi:10.1101/2023.02.27.530266

bioRxiv · 10.1101/2023.02.27.530266

Salmonella Typhimurium effector SseI regulates host peroxisomal dynamics to acquire lysosomal cholesterol for better intracellular growth

Raj, D.·Nair, A. V.·Sharma, J.·Prakash, S.·Kaushik, A.·Basu, S.·Sahu, S.·Singh, S.·Bhosale, V.·Chandra, T.·Ghoshal, U. C.·Dasgupta, A.·Siddiqi, M. I.·Gupta, S. K.·Chakravortty, D.·Ammanathan, V.·LAHIRI, A.

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Abstract

Intracellular Salmonella resides and multiplies in cholesterol-rich specialized compartment called Salmonella-containing vacuoles (SCVs) and avoids fusion with acidic lysosomes. Given, lysosomes are primary organelle that redistributes LDL derived cholesterol to other organelles; we questioned how lysosomal cholesterol can be transported to SCV. We demonstrate here that peroxisomes are recruited to SCVs in human primary macrophages, epithelial cells and functions as pro-bacterial organelles. Further, this interaction is assisted by SseI, a Salmonella effector protein containing mammalian peroxisome targeting sequence. SseI localizes to peroxisome, interacts and activates a host Ras GTPase, ARF-1 on the peroxisome membrane. Activation of ARF-1 leads to recruitment of phosphatidylinsolitol-5- phosphate-4 kinase to generate phosphatidylinsolitol-4-5-bisphosphate on peroxisomes. Accordingly, the{Delta} sseI strain showed reduced virulence in cell lines and during mice infection. Taken together, our work identified a fascinating mechanism by which a pathogen targets host organelles via its secretory effectors and exploits host metabolic intermediates for its intracellular proliferation.

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Raj, D., Nair, A. V., Sharma, J., Prakash, S., Kaushik, A., Basu, S., Sahu, S., Singh, S., Bhosale, V., Chandra, T., Ghoshal, U. C., Dasgupta, A., Siddiqi, M. I., Gupta, S. K., Chakravortty, D., Ammanathan, V., LAHIRI, A.. 2023-02-27. Salmonella Typhimurium effector SseI regulates host peroxisomal dynamics to acquire lysosomal cholesterol for better intracellular growth. https://doi.org/10.1101/2023.02.27.530266

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