2021 Fiscal Year Annual Research Report
Maintenance of intestinal homeostasis by deubiquitinase PTUD3
| Project/Area Number |
21F21112
|
|---|
| Research Institution | Osaka University |
|---|
Principal Investigator |
竹田 潔 大阪大学, 医学系研究科, 教授 (20309446)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
LI BO 大阪大学, 医学(系)研究科(研究院), 外国人特別研究員
|
|---|
| Project Period (FY) |
2021-04-28 – 2023-03-31
|
| Keywords | intestine / stromal cell / ubiquitination |
|---|
| Outline of Annual Research Achievements |
To determine Otud3 deficiency in which kind of cells contributes to the more severe colitis phenotype, we made use of different cell specific Otud3 KO mice. Deletion of Otud3 in epithelial cells or myeloid cells did not lead to exaggeration of colitis. Deletion of Otud3 on in Pdgfra+ stromal cells led to exaggeration of colitis. Expression of cytokines of the lamina propria was also upregulated in Pdgfa-cre; Otud3 flox/flox mice compared with Otud3 flox/flox mice.
We found that ulcerative colitis (UC) related Otud3 mutant protein could not remove K27-linked polyubiquitination on STING, and resulted in enhancement of TBK1 and IRF3 phosphorylation, and finally induced expression of IFN-beta and pro-inflammatory cytokines in in vitro study.
We found that commensal bacteria mediated activation of the STING/type I IFN pathway in colonic stromal cells.
|
| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
We think we could have data in experiments, which we originally planed.
|
| Strategy for Future Research Activity |
To clarify the mechanism behind, I plan to isolate Pdgfra＋ stromal cells from colon of Pdgfra-cre; Otud3 flox/flox and Otud3 flox/flox mice, then analyze these cell by single cell RNA-seq.
We will generate UC related Otud3 mutant mice and analyze their susceptibility to DSS-induced colitis. I will confirm if K27-linked polyubiquitination is enhanced, and STING type I IFN pathway is activated in the colonic stromal cells of UC related Otud3 mutant mice.
We will find out what commensal bacteria derived factors are involved, how those commensal bacteria derived factors activate sting type I IFN pathway in colonic stromal cells.
We plan to extend my research to human samples.
|
-
[Journal Article] The ATP-hydrolyzing ectoenzyme E-NTPD8 attenuates colitis through modulation of P2X4 receptor-dependent metabolism in myeloid cells.2021
Author(s)
Tani H, Li B, Kusu T, Okumura R, Nishimura J, Okuzaki D, Motooka D, Arakawa S, Yoshihara T, Ogino T, Tsai SH, Furuta Y, Muneta M, Nakamura S, Fukusaki E, Yamamoto K, Yagita H, Kayama H and Takeda K
-
Journal Title
Proc. Natl. Acad. Sci. USA
Volume: 118
Pages: e2100594118
DOI
Peer Reviewed
-
