Abstract
During infection, Salmonella species inject multiple type III secretion system (T3SS) effector proteins into host cells that mediate invasion and subsequent intracellular replication. At early stages of infection, Salmonella exploits key regulators of host intracellular vesicle transport, including the small GTPases Rab5 and Rab7, to subvert host endocytic vesicle trafficking and establish the Salmonella-containing vacuole (SCV). At later stages of intracellular replication, interactions of the SCV with Rab GTPases are less well defined. Here we report that Rab1, Rab5, and Rab11 are modified at later stages of Salmonella infection by SseK3, an arginine N-acetylglucosamine (GlcNAc) transferase effector translocated via the Salmonella pathogenicity island 2 (SPI-2) type III secretion system. SseK3 modified arginines at positions 74, 82, and 111 within Rab1 and this modification occurred independently of Rab1 nucleotide binding. SseK3 exhibited Golgi localization that was independent of its glycosyltransferase activity but Arg-GlcNAc transferase activity was required for inhibition of alkaline phosphatase secretion in transfected cells. While SseK3 had a modest effect on SEAP secretion during infection of HeLa229 cells, inhibition of IL-1 and GM-CSF cytokine secretion was only observed upon over-expression of SseK3 during infection of RAW264.7 cells. Our results suggest that, in addition to targeting death receptor signaling, SseK3 may contribute to Salmonella infection by interfering with the activity of key Rab GTPases.
Highlights
As Rab1 mediates vesicle transport from the ER to Golgi early in the secretory pathway, we explored the functional consequences of Arg-GlcNAcylation on Rab1 activity by testing whether the SseK family of proteins inhibited host protein secretion
Rab GTPases are well known for their role in mediating endocytosis and exocytosis as well as other intracellular membrane trafficking events
Rab5 is recruited to the Salmonella-containing vacuole (SCV) by the Salmonella pathogenicity island 1 (SPI-1) effector SopB, which is a phosphoinositide phosphatase (Mallo et al, 2008), while another SPI-1 effector, SopE, functions as a guanine exchange factor (GEF) for Rab5 and promotes the formation of GTP-bound active Rab5 on the SCV (Mukherjee et al, 2001)
Summary
Salmonella pathogenicity island 1 (SPI-1) and Salmonella pathogenicity island 2 (SPI-2) both encode type III secretion systems (T3SSs) that deliver virulence effector proteins into host cells that facilitate Salmonella pathogenesis. These two T3SSs are regulated in a spatio-temporal dependent. The SPI-1-encoded T3SS is activated initially, inducing inflammation and host cytoskeletal rearrangements to promote invasion of the bacteria into epithelial cells, while cells such as macrophages internalize Salmonella by phagocytosis. The SPI2-encoded T3SS is activated to establish a membrane-bound replicative niche termed the Salmonella-containing vacuole (SCV). The SCV subverts the canonical endolysosomal pathway to facilitate intracellular bacterial survival and replication (Ramsden et al, 2007; Jennings et al, 2017)
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