VANGL2 alleviates inflammatory bowel disease by recruiting the ubiquitin ligase MARCH8 to limit NLRP3 inflammasome activation through OPTN-mediated selective autophagy.
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 Van-Gogh-like 2 (VANGL2)...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2025-02-01
|
| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3002961 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1825199300445995008 |
|---|---|
| author | Huaji Jiang Yingchao Xie Zhiqiang Hu Jiansen Lu Jiahuan Zhang Hongyu Li Ke Zeng Wenqiang Peng Cheng Yang Junsheng Huang Zelong Han Xiaochun Bai Xiao Yu |
| author_facet | Huaji Jiang Yingchao Xie Zhiqiang Hu Jiansen Lu Jiahuan Zhang Hongyu Li Ke Zeng Wenqiang Peng Cheng Yang Junsheng Huang Zelong Han Xiaochun Bai Xiao Yu |
| author_sort | Huaji Jiang |
| collection | DOAJ |
| description | 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 Van-Gogh-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. |
| format | Article |
| id | doaj-art-eedeef48144548218981aff6d6952858 |
| institution | Kabale University |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-eedeef48144548218981aff6d69528582025-02-08T05:30:20ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852025-02-01232e300296110.1371/journal.pbio.3002961VANGL2 alleviates inflammatory bowel disease by recruiting the ubiquitin ligase MARCH8 to limit NLRP3 inflammasome activation through OPTN-mediated selective autophagy.Huaji JiangYingchao XieZhiqiang HuJiansen LuJiahuan ZhangHongyu LiKe ZengWenqiang PengCheng YangJunsheng HuangZelong HanXiaochun BaiXiao YuInflammatory 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 Van-Gogh-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.https://doi.org/10.1371/journal.pbio.3002961 |
| spellingShingle | Huaji Jiang Yingchao Xie Zhiqiang Hu Jiansen Lu Jiahuan Zhang Hongyu Li Ke Zeng Wenqiang Peng Cheng Yang Junsheng Huang Zelong Han Xiaochun Bai Xiao Yu VANGL2 alleviates inflammatory bowel disease by recruiting the ubiquitin ligase MARCH8 to limit NLRP3 inflammasome activation through OPTN-mediated selective autophagy. PLoS Biology |
| title | VANGL2 alleviates inflammatory bowel disease by recruiting the ubiquitin ligase MARCH8 to limit NLRP3 inflammasome activation through OPTN-mediated selective autophagy. |
| title_full | VANGL2 alleviates inflammatory bowel disease by recruiting the ubiquitin ligase MARCH8 to limit NLRP3 inflammasome activation through OPTN-mediated selective autophagy. |
| title_fullStr | VANGL2 alleviates inflammatory bowel disease by recruiting the ubiquitin ligase MARCH8 to limit NLRP3 inflammasome activation through OPTN-mediated selective autophagy. |
| title_full_unstemmed | VANGL2 alleviates inflammatory bowel disease by recruiting the ubiquitin ligase MARCH8 to limit NLRP3 inflammasome activation through OPTN-mediated selective autophagy. |
| title_short | VANGL2 alleviates inflammatory bowel disease by recruiting the ubiquitin ligase MARCH8 to limit NLRP3 inflammasome activation through OPTN-mediated selective autophagy. |
| title_sort | vangl2 alleviates inflammatory bowel disease by recruiting the ubiquitin ligase march8 to limit nlrp3 inflammasome activation through optn mediated selective autophagy |
| url | https://doi.org/10.1371/journal.pbio.3002961 |
| work_keys_str_mv | AT huajijiang vangl2alleviatesinflammatoryboweldiseasebyrecruitingtheubiquitinligasemarch8tolimitnlrp3inflammasomeactivationthroughoptnmediatedselectiveautophagy AT yingchaoxie vangl2alleviatesinflammatoryboweldiseasebyrecruitingtheubiquitinligasemarch8tolimitnlrp3inflammasomeactivationthroughoptnmediatedselectiveautophagy AT zhiqianghu vangl2alleviatesinflammatoryboweldiseasebyrecruitingtheubiquitinligasemarch8tolimitnlrp3inflammasomeactivationthroughoptnmediatedselectiveautophagy AT jiansenlu vangl2alleviatesinflammatoryboweldiseasebyrecruitingtheubiquitinligasemarch8tolimitnlrp3inflammasomeactivationthroughoptnmediatedselectiveautophagy AT jiahuanzhang vangl2alleviatesinflammatoryboweldiseasebyrecruitingtheubiquitinligasemarch8tolimitnlrp3inflammasomeactivationthroughoptnmediatedselectiveautophagy AT hongyuli vangl2alleviatesinflammatoryboweldiseasebyrecruitingtheubiquitinligasemarch8tolimitnlrp3inflammasomeactivationthroughoptnmediatedselectiveautophagy AT kezeng vangl2alleviatesinflammatoryboweldiseasebyrecruitingtheubiquitinligasemarch8tolimitnlrp3inflammasomeactivationthroughoptnmediatedselectiveautophagy AT wenqiangpeng vangl2alleviatesinflammatoryboweldiseasebyrecruitingtheubiquitinligasemarch8tolimitnlrp3inflammasomeactivationthroughoptnmediatedselectiveautophagy AT chengyang vangl2alleviatesinflammatoryboweldiseasebyrecruitingtheubiquitinligasemarch8tolimitnlrp3inflammasomeactivationthroughoptnmediatedselectiveautophagy AT junshenghuang vangl2alleviatesinflammatoryboweldiseasebyrecruitingtheubiquitinligasemarch8tolimitnlrp3inflammasomeactivationthroughoptnmediatedselectiveautophagy AT zelonghan vangl2alleviatesinflammatoryboweldiseasebyrecruitingtheubiquitinligasemarch8tolimitnlrp3inflammasomeactivationthroughoptnmediatedselectiveautophagy AT xiaochunbai vangl2alleviatesinflammatoryboweldiseasebyrecruitingtheubiquitinligasemarch8tolimitnlrp3inflammasomeactivationthroughoptnmediatedselectiveautophagy AT xiaoyu vangl2alleviatesinflammatoryboweldiseasebyrecruitingtheubiquitinligasemarch8tolimitnlrp3inflammasomeactivationthroughoptnmediatedselectiveautophagy |