Salmonella Typhimurium effector SseI regulates host peroxisomal dynamics to acquire lysosomal cholesterol
Salmonella enterica serotype Typhimurium (Salmonella) resides and multiplies intracellularly in cholesterol-rich compartments called Salmonella-containing vacuoles (SCVs) with actin-rich tubular extensions known as Salmonella-induced filaments (SIFs). SCV maturation depends on host-derived cholesterol, but the transport mechanism of low-density lipoprotein (LDL)-derived cholesterol to SCVs remains unclear. Here we find that peroxisomes are recruited to SCVs and function as pro-bacterial organelle. The Salmonella effector protein SseI is required for the interaction between peroxisomes and the SCV. SseI contains a variant of the PTS1 peroxisome-targeting sequence, GKM, localizes to the peroxisomes and activates the host Ras GTPase, ADP-ribosylation factor-1 (ARF-1). Activation of ARF-1 leads to the recruitment of phosphatidylinsolitol-5-phosphate-4 kinase and the generation of phosphatidylinsolitol-4-5-bisphosphate on peroxisomes. This enhances the interaction of peroxisomes with lysosomes and allows for the transfer of lysosomal cholesterol to SCVs using peroxisomes as a bridge. Salmonella infection of peroxisome-depleted cells leads to the depletion of cholesterol on the SCVs, resulting in reduced SIF formation and bacterial proliferation. Taken together, our work identified peroxisomes as a target of Salmonella secretory effectors, and as conveyance of host cholesterol to enhance SCV stability, SIF integrity, and intracellular bacterial growth.
Authors
- Amit Lahiri (ORCID: https://orcid.org/0000-0003-2391-1301)
- Sonia Verma (ORCID: https://orcid.org/0000-0001-5920-7792)
- Rajdeep Guha (ORCID: https://orcid.org/0000-0002-4451-6995)
- Veena Ammanathan (ORCID: https://orcid.org/0000-0002-5142-380X)
- Suresh Kumar Sharma (ORCID: https://orcid.org/0000-0002-5054-6170)
- Desh Raj (ORCID: https://orcid.org/0000-0003-4448-2585)
- Uday C. Ghoshal (ORCID: https://orcid.org/0000-0003-0221-8495)
- Dipshikha Chakravortty (ORCID: https://orcid.org/0000-0002-7838-5145)
- Tulika Chandra (ORCID: https://orcid.org/0000-0002-6807-1759)
- Swarnali Basu
- Aman Chandra Kaushik (ORCID: https://orcid.org/0000-0001-7346-0970)
- Shakti Prakash (ORCID: https://orcid.org/0000-0002-8273-6606)
- Vivek Bhosale (ORCID: https://orcid.org/0000-0002-2729-266X)
- Shriya Singh (ORCID: https://orcid.org/0000-0003-0397-5498)
- Anmol Singh (ORCID: https://orcid.org/0000-0001-9320-320X)
- Mohammad Imran Siddiqi (ORCID: https://orcid.org/0000-0001-5655-5484)
- Abhilash Vijay Nair (ORCID: https://orcid.org/0000-0002-0822-7651)
- Jyotsna Sharma (ORCID: https://orcid.org/0000-0002-6254-9512)
- Shiva Sharma
- S. K. Gupta (ORCID: https://orcid.org/0000-0002-6770-0760)
- Amitava Dasgupta (ORCID: https://orcid.org/0000-0001-9014-1904)
- Simran
- Kabita Sarkar
- Shikha Sahu
- Manisha Rathore
Institutions
- Sanjay Gandhi Post Graduate Institute of Medical Sciences (IN)
- Central Drug Research Institute (IN)
- King George's Medical University (IN)
- Indian Institute of Science Bangalore (IN)
- Academy of Scientific and Innovative Research (IN)
Publication Details
- Journal
- EMBO Reports
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1038/s44319-024-00328-x
- Citations
- 8
- Primary Topic
- Peroxisome Proliferator-Activated Receptors
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- Indian Institute of Science
- Wellcome Trust
- Department of Biotechnology, Ministry of Science and Technology, India
- Indian Council of Medical Research
- Council of Scientific and Industrial Research, India
- Ministry of Earth Sciences
- The Wellcome Trust DBT India Alliance
- University of California, San Diego
- Science and Engineering Research Board
- Central Drug Research Institute