The role of the Siglec-G ITIM domain during bacterial infection

Abstract

Siglecs, membrane-bound lectins of the sialic acid-binding immunoglobulin superfamily, inhibit immune responses by recruiting tyrosine phosphatases (e.g., SHP-1 and SHP-2) through their cytoplasmic immunoreceptor tyrosine-based inhibition motif (ITIM) domain. The role of Siglecs in infection has been extensively studied, but downstream signaling through the ITIM domain remains unclear. Here, we used a GST pull-down assay to identify additional proteins associated with the ITIM domain during bacterial infection. Gdi2 bound to ITIM under normal homeostasis, but Rab1a was recruited to ITIM during bacterial infection. Western blot analysis confirmed the presence of SHP-1 and SHP-2 in eluted ITIM-associated proteins under normal homeostasis. We confirmed the association of ITIM with Gdi2 or Rab1a by transfection of corresponding expression vectors in 293T cells followed by immunoprecipitation-western blot assay. Thus, ITIM’s role in the inhibition of the immune response during bacterial infection may be regulated by interaction with Gdi2 and Rab1a in addition to SHP-1 and SHP-2.

Targeted disruption of Rab1a causes early embryonic lethality

“…Recently, the authors demonstrated that Rab1a bound to the ITIM domain of Siglec-G under normal homeostasis. By contrast, Rab1a was recruited to the ITIM domain during bacterial infection, suggesting that GDI2 and Rab1a may regulate immune response through interaction with the ITIM domain during bacterial infection ( 18 ). In the present study, to investigate whether Rab1a plays a role during bacterial infection, WT and Rab1a +/− mice were challenged with 10 mg/kg LPS and collected serum from the mice as previously described ( 21 , 22 , 24 ).…”

“…The authors have previously demonstrated that Rab1a may regulate the immune response through interaction with the ITIM domain during bacterial infection in vitro ( 18 ). To further investigate the function of Rab1a in vivo , the present study generated mice with a trapped Rab1a gene and uncovered a novel role for Rab1a during early embryonic development in mice.…”

“…In a recent study, it was demonstrated by the authors that GDI2 binds to the immunoreceptor tyrosine-based inhibitory motif (ITIM) domain of sialic acid-binding immunoglobulin-type lectin G (Siglec-G) in hematopoietic cells, such as B-1a cells under conditions of normal homeostasis, whereas Rab1a is recruited to the ITIM domain during bacterial infection ( 18 ). Therefore, it was hypothesized that GDI2 and Rab1a may regulate the immune response through interaction with the ITIM domain during bacterial infection.…”

Clinical Management of Cerebral Aneurysms

“…Recent research on the inflammatory mechanism of cerebral aneurysm has revealed that inflammatory cells infiltrate and destroy the elastic and collagen fibers of the cerebral artery wall, resulting in the disease's progression. The main cells involved are macrophages, where monocyte chemotactic protein-1 (MCP-1) regulates the expression of pro-inflammatory genes such as MCP-1, and nuclear factor-xb (NF-B), which transcriptionally regulates the expression of pro-inflammatory genes the same as MCP-1, and matrix metalloproteinases (MMPs), particularly MMP-9, are abnormally highly expressed [9]. NF-κB is involved in the inflammatory response and plays a regulatory role.…”