The Salmonella effector protein SifA plays a dual role in virulence

Abstract

The virulence of Salmonella relies on the expression of effector proteins that the bacterium injects inside infected cells. Salmonella enters eukaryotic cells and resides in a vacuolar compartment on which a number of effector proteins such as SifA are found. SifA plays an essential role in Salmonella virulence. It is made of two distinct domains. The N-terminal domain of SifA interacts with the host protein SKIP. This interaction regulates vacuolar membrane dynamics. The C-terminal has a fold similar to other bacterial effector domains having a guanine nucleotide exchange factor activity. Although SifA interacts with RhoA, it does not stimulate the dissociation of GDP and the activation of this GTPase. Hence it remains unknown whether the C-terminal domain contributes to the function of SifA in virulence. We used a model of SKIP knockout mice to show that this protein mediates the host susceptibility to salmonellosis and to establish that SifA also contributes to Salmonella virulence independently of its interaction with SKIP. We establish that the C-terminal domain of SifA mediates this SKIP-independent contribution. Moreover, we show that the two domains of SifA are functionally linked and participate to the same signalling cascade that supports Salmonella virulence.

Role of the ESCRT‐III complex in controlling integrity of the Salmonella ‐containing vacuole

“…The lack of either SifA or SKIP leads to a deficiency in SIF formation, affecting SCV integrity and resulting in bacterial release into the host cell cytosol. This leads to cytosolic hyper‐replication in epithelial cells and reduced intracellular proliferation in macrophages (Beuzon et al, ; Boucrot et al, ; Zhao et al, ). The reorganisation of the host endocytic pathway leads to a recruitment of endosomal compartments to the SCV.…”

Cellular evasion strategies of Helicobacter pylori in regulating its intracellular fate

“…While Rab proteins serve as one of the key targets for pathogens, other molecules are also triggered by pathogens to manipulate the host's cytoplasmic trafficking. Salmonella secretes secretor effector protein (SifA) via its type 3 secretion system (T3SS) from the Salmonella-containing vacuoles to the cytoplasm [87]. SifA then binds to kinesin-interacting protein (SKIP), a host protein, which downregulates the recruitment of kinesin to the bacterial vacuoles, thereby promoting the membrane dynamics of vacuoles [88].…”

Bacterial secretion systems and regulation of inflammasome activation

“…SPI-2 drives the expression of the Spi/Ssa T3SS, which the bacterium uses to secrete effector proteins that help it persist in its vacuolar niche. One secreted protein, SifA, induces stabilization of the vacuole by microtubules and is critically important for virulence [71,128]. Yet, the Spi/Ssa T3SS, which is required by the bacteria for virulence, also activates inflammasome pathways by the mechanisms described above and results in the eventual clearance of the pathogen.…”