2. Academic Validation
  3. Salmonella exploits LRRK2-dependent plasma membrane dynamics to invade host cells

Salmonella exploits LRRK2-dependent plasma membrane dynamics to invade host cells

  • Nat Commun. 2025 Mar 8;16(1):2329. doi: 10.1038/s41467-025-57453-x.
Hongxian Zhu 1 2,  Andrew M Sydor 1,  Bing-Ru Yan 1,  Ren Li 1,  Michal T Boniecki 3,  Carina Lyons 1 2,  Miroslaw Cygler 3,  Aleixo M Muise 1 4 5 6,  Michelle E Maxson 1 7,  Sergio Grinstein 1 4 8,  Brian Raught 9 10,  John H Brumell 11 12 13 14
Affiliations

Affiliations

  • 1 Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.
  • 2 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 3 Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada.
  • 4 Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
  • 5 Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada.
  • 6 SickKids IBD Centre, Hospital for Sick Children, Toronto, ON, Canada.
  • 7 Department of Immunology, University of Toronto, Toronto, ON, Canada.
  • 8 Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
  • 9 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • 10 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • 11 Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada. john.brumell@sickkids.ca.
  • 12 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. john.brumell@sickkids.ca.
  • 13 SickKids IBD Centre, Hospital for Sick Children, Toronto, ON, Canada. john.brumell@sickkids.ca.
  • 14 Institute of Medical Science, University of Toronto, Toronto, ON, Canada. john.brumell@sickkids.ca.
PMID: 40057496 DOI: 10.1038/s41467-025-57453-x
Abstract

Salmonella utilizes type 3 secreted effector proteins to induce plasma membrane (PM) perturbations during invasion of host cells1. The effectors drive mobilization of host membranes to generate cell surface ruffles, followed by invagination and scission of the PM to generate Salmonella-containing vacuoles (SCVs)2. Here, we show that LRRK2 kinase generates membrane reservoirs exploited by Salmonella during invasion. The reservoirs are tubular compartments associated with the PM under basal conditions and are formed through the phosphorylation of RAB10 GTPase by LRRK2. Mobilization of membrane reservoirs to generate invasion ruffles mediates delivery of phosphorylated RAB10 to invasion sites. Subsequently, RAB10 dephosphorylation is required for its inactivation by a Bacterial GTPase activating protein and subsequent scission of the PM. RAB10 dephosphorylation is mediated by a TLR4/PIEZO1/TMEM16F-dependent pathway and is inhibited by hyperactive variants of LRRK2. Our findings reveal how Salmonella exploits LRRK2-dependent PM dynamics during invasion and provide new insight into how LRRK2 variants can protect against Bacterial infection3,4.

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