Submission ID 93699

Poster Code HR-P-15
Title of Abstract The tyrosine phosphatase Shp-2 is an important regulator of Toll-like receptors.
Abstract Submission Intro. Polymorphisms in SHP-2 gene were reported in patients with ulcerative colitis. How Shp-2 contributes to colitis is still unclear. Interestingly, intestinal epithelial cell (IEC)-specific deletion of Shp-2 results in severe colitis in mice (Shp-2IEC-KO). Notably, we found important alterations in the gut microbiota composition that preceded colitis. Antibiotherapy or epithelial KO of Myd88 (an adaptor of Toll-like receptors) inhibits colitis in these mice suggesting that microbiota alterations contribute to colitis development. We then speculated that Shp-2 might be an important regulator of TLR signaling pathways. Methods. We analyzed the possible activation of Shp-2 in IEC-6 cells exposed to TLR ligands. The contribution of Shp-2 was tested by using a specific allosteric inhibitor (SHP-099, 10 M). To identify the molecular mechanisms by which Shp-2 regulates TLR signaling, the APEX2 proximity assay was used, in combination with mass spectrometry. Results. 1- Shp-2 is rapidly phosphorylated (Y542) upon stimulation of IEC-6 with TLR ligands including LPS (TLR4), flagellin (TLR5), poly IC (TLR3), Pam-2 (TLR2), CpG-B (TLR9). 2- Pre-treatment of cells with the Shp-2 inhibitor SHP099 inhibits ERK/MAPK and p65/NFkB phosphorylation induced by LPS and CpG-B. 3- APEX2 proximity labeling identifies 33 proteins as Shp-2 putative interactors. When all Shp-2 neighbors are analyzed by "Pathway Enrichment Analysis" with the Reactome database, those pathways related to adaptive and innate immune system, as well as to positive regulation of NFB pathway signaling are among the most significant pathways associated with Shp-2. Of note, the top Shp-2 interactor is DHX9 (103,3 fold change), an helicase that senses CpG-B (TLR9 ligand) and which is thus critical for sensing viral DNA pathogens in order to trigger differential cytokine responses. Conclusion. These data thus suggest that Shp-2 tightly regulates TLR/Myd88 signaling. Experiments are in progress to validate Shp-2 interactome upon TLR stimulation.
Please indicate who nominated you Nathalie Rivard
What Canadian Institutes of Health Research (CIHR) institute is your research most closely aligned? Infection and Immunity
What Canadian Institutes of Health Research (CIHR) pillar of health research does your research fall under? Biomedical
PDF of abstract CHABOT_VICTOR_Abstract_ICAM2023.pdf
2023-02-16 at 20:17:17
Presenter and Author(s) Victor Chabot
Jessica Gagné-Sansfaçon
Victor Chabot
Valérie Lannoy
Nathalie Rivard

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