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Published on: September 19, 2013
Salmonella exploits LRRK2-dependent plasma membrane dynamics to invade host cells
Hongxian Zhu1,2, Andrew M Sydor1, Bing-Ru Yan1
1Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.
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.
Insights
Salmonella invasion hijacks host cell membrane reservoirs generated by LRRK2 kinase. This process involves RAB10 GTPase phosphorylation and dephosphorylation, revealing new insights into bacterial infection mechanisms.
Area of Science:
- Cell biology
- Microbiology
- Molecular biology
Background:
- Salmonella Typhimurium uses type 3 secreted effector proteins to manipulate host cell plasma membranes (PM) during invasion.
- This manipulation involves the formation of Salmonella-containing vacuoles (SCVs) through membrane ruffling, invagination, and scission.
Purpose of the Study:
- To investigate the role of Leucine-rich repeat kinase 2 (LRRK2) in Salmonella invasion.
- To elucidate the mechanism by which LRRK2 kinase activity and RAB10 GTPase regulate host cell membrane dynamics during bacterial entry.
Main Methods:
- Investigated the formation and function of LRRK2-dependent membrane reservoirs.
- Analyzed the phosphorylation status of RAB10 GTPase during Salmonella invasion.
- Examined the role of TLR4/PIEZO1/TMEM16F pathway in RAB10 dephosphorylation.
- Assessed the impact of hyperactive LRRK2 variants on bacterial invasion.
Main Results:
- LRRK2 kinase generates tubular membrane reservoirs associated with the PM.
- These reservoirs are mobilized during invasion, delivering phosphorylated RAB10 to facilitate Salmonella entry.
- RAB10 dephosphorylation, mediated by a TLR4/PIEZO1/TMEM16F pathway, is crucial for PM scission and bacterial internalization.
- Hyperactive LRRK2 variants inhibit RAB10 dephosphorylation, potentially conferring protection against Salmonella infection.
Conclusions:
- Salmonella exploits LRRK2-dependent membrane reservoirs and RAB10 GTPase dynamics for host cell invasion.
- The interplay between LRRK2, RAB10, and specific signaling pathways governs PM remodeling during bacterial entry.
- Understanding these mechanisms offers insights into host-pathogen interactions and potential therapeutic strategies targeting LRRK2.
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