Salmonella Typhimurium effector SseI regulates host peroxisomal dynamics to acquire lysosomal cholesterol

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Abstract
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.
Funding Information
  • Wellcome Trust DBT India Alliance (IA/E/21/1/506319)
  • Anusandhan National Research Foundation (PDF/2021/002843 SRG/2019/000268)
  • Indian Council of Medical Research (AD HOC (ORTHO) 2022-NCD-1)
  • Council of Scientific and Industrial Research, India (MLP2105,HCP0047,Director-CDRI)

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