PLEKHM1 Regulates Salmonella-Containing Vacuole Biogenesis and Infection

Abstract

The host endolysosomal compartment is often manipulated by intracellular bacterial pathogens. Salmonella (Salmonella enterica serovar Typhimurium) secrete numerous effector proteins, including SifA, through a specialized type III secretion system to hijack the host endosomal system and generate the Salmonella-containing vacuole (SCV). To form this replicative niche, Salmonella targets the Rab7 GTPase to recruit host membranes through largely unknown mechanisms. We show that Pleckstrin homology domain-containing protein family member 1 (PLEKHM1), a lysosomal adaptor, is targeted by Salmonella through direct interaction with SifA. By binding the PLEKHM1 PH2 domain, Salmonella utilize a complex containing PLEKHM1, Rab7, and the HOPS tethering complex to mobilize phagolysosomal membranes to the SCV. Depletion of PLEKHM1 causes a profound defect in SCV morphology with multiple bacteria accumulating in enlarged structures and significantly dampens Salmonella proliferation in multiple cell types and mice. Thus, PLEKHM1 provides a critical interface between pathogenic infection and the host endolysosomal system.

Characterization of the Mammalian CORVET and HOPS Complexes and Their Modular Restructuring for Endosome Specificity

“…3G). The N terminus of yeast vps39 that binds Ypt7 is poorly conserved in the mammalian VPS39 ortholog, which might explain why the mammalian HOPS complex has shifted to bind RAB7 effectors such as RILP (30,32) and PLEKHM1 (14,15). The HOPS complex binds RILP on either side of the complex (VPS39/VPS11 in the tail and VPS41/VPS18 in the head) and may bridge RILP molecules on opposing vesicles.…”

“…Because VPS33A in the head of HOPS also binds to SNAREs (41), a connection between two vesicles will then support tethering and subsequent fusion. It is interesting to note that the HOPS complex can also bind the GTPase Arl8b on lysosomes (20,42) and PLEKHM1 on LE, phagosomes, and autophagosomes (14,15), possibly tethering these vesicles with RILP-containing organelles (Fig. 6B).…”

Characterization of a Relatively Malignant Form of Osteopetrosis Caused by a Novel Mutation in the PLEKHM1 Gene

“…The RH domain was demonstrated to participate in intracellular signaling pathways via its interaction with Rab7, (21,22,(30)(31)(32) suggesting that PLEKHM1 might be involved in intracellular vesicular transport. Another RH domain-containing protein, Rubicon, has also been found to link the endosomal and autophagic pathways.…”

“…Additionally, based on the contradictory results from different research groups using different cell types, the result is likely due to different intervention methods and cell backgrounds. (22,23,34) Further investigations are needed to determine the roles of PLEKHM1 in other cell types.…”

“…(17)(18)(19)(20) However, different research groups studying different cell lines showed controversial results regarding the function of PLEKHM1 in vesicle trafficking. (15,16,(21)(22)(23) Therefore, the precise function of PLEKHM1 remains unclear, and the genotype-phenotype correlations regarding PLEKHM1 mutations have not been established due to their rarity.…”