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

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.