Rac and Rab GTPases dual effector Nischarin regulates vesicle maturation to facilitate survival of intracellular bacteria

Abstract

The intracellular pathogenic bacterium Salmonella enterica serovar typhimurium (Salmonella) relies on acidification of the Salmonella‐containing vacuole (SCV) for survival inside host cells. The transport and fusion of membrane‐bound compartments in a cell is regulated by small GTPases, including Rac and members of the Rab GTPase family, and their effector proteins. However, the role of these components in survival of intracellular pathogens is not completely understood. Here, we identify Nischarin as a novel dual effector that can interact with members of Rac and Rab GTPase (Rab4, Rab14 and Rab9) families at different endosomal compartments. Nischarin interacts with GTP‐bound Rab14 and PI(3)P to direct the maturation of early endosomes to Rab9/CD63‐containing late endosomes. Nischarin is recruited to the SCV in a Rab14‐dependent manner and enhances acidification of the SCV. Depletion of Nischarin or the Nischarin binding partners—Rac1, Rab14 and Rab9 GTPases—reduced the intracellular growth of Salmonella. Thus, interaction of Nischarin with GTPases may regulate maturation and subsequent acidification of vacuoles produced after phagocytosis of pathogens.

Rab2a and Rab27a cooperatively regulate the transition from granule maturation to exocytosis through the dual effector Noc2

“…The mode of the complex formation between these three proteins appears to be unique. Although some Rab effector proteins are known to interact with different Rab proteins, such as RUFY1 (Yamamoto et al, 2010), nischarin (Kuij et al, 2013) and golgin family proteins (Gillingham and Munro, 2016), they do so separately or sequentially. There is no reported instance in which the same effector molecule simultaneously binds two different Rab proteins.…”

A post-GWAS analysis of predicted regulatory variants and tuberculosis susceptibility

“…Nischarin has recently been identified as a dual effector that interacts with members of the Rac and Rab GTPase families [46]. The regulation of GTPases by Nischarin may regulate the maturation and acidification of vacuoles that are associated with phagocytosis of bacterial pathogens [46]. The odds ratio associated with the variant indicated an increased risk of progressing to active TB.…”

Proteomes of Host Cell Membranes Modified by Intracellular Activities of Salmonella enterica

“…A subset of host cell proteins identified in our SMM proteome survey have previously been reported as associated with or involved in the biogenesis of SCVs or SIFs. These include GTPases Rab7a, Rab5c, Rab11a, and Rab14 (39,40); filamin (41); myosin II (42); dynein (36); desmoplakin (43); and actin (44).…”