VANGL2 alleviates inflammatory bowel disease by recruiting the ubiquitin ligase MARCH8 to limit NLRP3 inflammasome activation through OPTN-mediated selective autophagy
Jiang, Huaji
;
Xie, Yingchao
;
Hu, Zhiqiang
, et al.
PLoS Biol.,2025,23(2):e3002961.
DOI:
10.1371/journal.pbio.3002961
PubMed ID:
39899477
More
Abstract: Inflammatory bowel disease (IBD) is a chronic and potentially life-threatening inflammatory disease of gastroenteric tissue characterized by episodes of intestinal inflammation, but the underlying mechanisms remain elusive. Here, we explore the role and precise mechanism of VanGogh-like 2 (VANGL2) during the pathogenesis of IBD. VANGL2 decreases in IBD patients and dextran sulfate sodium (DSS)-induced colitis in mice. Myeloid VANGL2 deficiency exacerbates the progression of DSS-induced colitis in mice and specifically enhances the activation of NLRP3 inflammasome in macrophages. NLRP3-specific inhibitor MCC950 effectively alleviates DSS-induced colitis in VANGL2 deficient mice. Mechanistically, VANGL2 interacts with NLRP3 and promotes the autophagic degradation of NLRP3 through enhancing the K27-linked polyubiquitination at lysine 823 of NLRP3 by recruiting E3 ligase MARCH8, leading to optineurin (OPTN)-mediated selective autophagy. Notably, decreased VANGL2 in the peripheral blood mononuclear cells from IBD patients results in overt NLRP3 inflammasome activation and sustained inflammation. Taken together, this study demonstrates that VANGL2 acts as a repressor of IBD progression by inhibiting NLRP3 inflammasome activation and provides insights into the crosstalk between inflammation and autophagy in preventing IBD.
Purchased from AmBeed:
133407-82-6
The?Toxoplasma?Effector GRA4 Hijacks Host TBK1 to Oppositely Regulate Anti-T. Gondii?Immunity and Tumor Immunotherapy
Zhiqiang Hu
;
?Yufen Zhang
;
?Yingchao Xie
, et al.
Adv. Sci.,2024,2400952.
DOI:
10.1002/advs.202400952
More
Abstract: Toxoplasma gondii (T. gondii)-associated polymorphic effector proteins are crucial in parasite development and regulating host anti-T. gondii immune responses. However, the mechanism remains obscure. Here, it is shown that Toxoplasma effector dense granules 4 (GRA4) restricts host IFN-I activation. Infection with ?gra4 mutant T. gondii strain induces stronger IFN-I responses and poses a severe threat to host health. Mechanistically, GRA4 binds to phosphorylated TBK1 to promote TRIM27-catalyzed K48-ubiquitination at Lys251/Lys372 residues, which enhances its recognition by autophagy receptor p62, ultimately leading to TBK1 autophagic degradation. Furthermore, an avirulent ?gra4 strain (ME49?ompdc/gra4) is constructed for tumor immunotherapy due to its ability to enhance IFN-I production. Earlier vaccination with ME49?ompdc/gra4 confers complete host resistance to the tumor compared with the classical ME49?ompdc treatment. Notably, ME49?ompdc/gra4 vaccination induces a specific CD64 +MAR-1 +CD11b + dendritic cell subset, thereby enhancing T cell anti-tumor responses. Overall, these findings identify the negative role of T. gondii GRA4 in modulating host IFN-I signaling and suggest that GRA4 can be a potential target for the development of T. gondii vaccines and tumor immunotherapy.
Keywords:
attenuated T. gondii ;
selective autophagy ;
toxoplasmosis ;
tumor therapy ;
type I interferon
Purchased from AmBeed:
133407-82-6
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
120K+ Compounds
Competitive Price
1-2 Day Shipping
