Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption.Dysregulation of this process leads to multiple diseases,including osteoporosis.However,the underlying...Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption.Dysregulation of this process leads to multiple diseases,including osteoporosis.However,the underlying molecular mechanisms are not fully understood.Here,we show that the global and conditional osteoblast knockout of a deubiquitinase Otub1 result in low bone mass and poor bone strength due to defects in osteogenic differentiation and mineralization.Mechanistically,the stability of FGFR2,a crucial regulator of osteogenesis,is maintained by OTUB1.OTUB1 attenuates the E3 ligase SMURF1-mediated FGFR2 ubiquitination by inhibiting SMURF1’s E2 binding.In the absence of OTUB1,FGFR2 is ubiquitinated excessively by SMURF1,followed by lysosomal degradation.Consistently,adeno-associated virus serotype 9(AAV9)-delivered FGFR2 in knee joints rescued the bone mass loss in osteoblast-specific Otub1-deleted mice.Moreover,Otub1 mRNA level was significantly downregulated in bones from osteoporotic mice,and restoring OTUB1 levels through an AAV9-delivered system in ovariectomy-induced osteoporotic mice attenuated osteopenia.Taken together,our results suggest that OTUB1 positively regulates osteogenic differentiation and mineralization in bone homeostasis by controlling FGFR2 stability,which provides an optical therapeutic strategy to alleviate osteoporosis.展开更多
The E3 ubiquitin ligase(E3)-mediated ubiquitination and deubiquitinase(DUB)-mediated deubiquitination processes are closely associated with the occurrence and development of colonic inflammation.Ovarian tumor deubiqui...The E3 ubiquitin ligase(E3)-mediated ubiquitination and deubiquitinase(DUB)-mediated deubiquitination processes are closely associated with the occurrence and development of colonic inflammation.Ovarian tumor deubiquitinase 1(OTUD1)is involved in immunoregulatory functions linked to infectious diseases.However,the effect of OTUD1 on intestinal immune responses during colonic inflammatory disorders such as inflammatory bowel disease(IBD)remains unclear.Here,we show that loss of OTUD1 in mice contributes to the pathogenesis of dextran sulfate sodium(DSS)-induced colitis via excessive release of proinflammatory cytokines.In addition,bone marrow transplantation experiments revealed that OTUD1 in hematopoietic cells plays a dominant role in protection against colitis.Mechanistically,OTUD1 physically interacts with receptor-interacting serine/threonine-protein kinase 1(RIPK1)and selectively cleaves K63-linked polyubiquitin chains from RIPK1 to inhibit the recruitment of NF-κB essential modulator(NEMO).Moreover,the expression of OTUD1 in mucosa samples from ulcerative colitis(UC)patients was lower than that in mucosa samples from healthy controls.Furthermore,we demonstrate that the UC-associated OTUD1 G430V mutation abolishes the ability of OTUD1 to inhibit RIPK1-mediated NF-κB activation and intestinal inflammation.Taken together,our study unveils a previously unexplored role of OTUD1 in moderating intestinal inflammation by inhibiting RIPK1-mediated NF-κB activation,suggesting that the OTUD1-RIPK1 axis could be a potential target for the treatment of IBD.展开更多
基金supported by the National Key Research and Development Project of China (2021YFA1300200)China Postdoctoral Science Foundation (2021T140797)+2 种基金the National Natural Science Foundation of China (82192881,81825014,31830003,32201023,81900765)the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29020000)the State Key Laboratory of Proteomics (SKLP-K202001).
文摘Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption.Dysregulation of this process leads to multiple diseases,including osteoporosis.However,the underlying molecular mechanisms are not fully understood.Here,we show that the global and conditional osteoblast knockout of a deubiquitinase Otub1 result in low bone mass and poor bone strength due to defects in osteogenic differentiation and mineralization.Mechanistically,the stability of FGFR2,a crucial regulator of osteogenesis,is maintained by OTUB1.OTUB1 attenuates the E3 ligase SMURF1-mediated FGFR2 ubiquitination by inhibiting SMURF1’s E2 binding.In the absence of OTUB1,FGFR2 is ubiquitinated excessively by SMURF1,followed by lysosomal degradation.Consistently,adeno-associated virus serotype 9(AAV9)-delivered FGFR2 in knee joints rescued the bone mass loss in osteoblast-specific Otub1-deleted mice.Moreover,Otub1 mRNA level was significantly downregulated in bones from osteoporotic mice,and restoring OTUB1 levels through an AAV9-delivered system in ovariectomy-induced osteoporotic mice attenuated osteopenia.Taken together,our results suggest that OTUB1 positively regulates osteogenic differentiation and mineralization in bone homeostasis by controlling FGFR2 stability,which provides an optical therapeutic strategy to alleviate osteoporosis.
基金supported by the National Key Research and Development Project of China(2021YFA1300200)the Biosafety Special Project of China(19SWAQ17),the National Natural Science Foundation of China(31800746,31830003 and 81825014)+1 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29020000)the State Key Laboratory of Proteomics(SKLP-K202001).
文摘The E3 ubiquitin ligase(E3)-mediated ubiquitination and deubiquitinase(DUB)-mediated deubiquitination processes are closely associated with the occurrence and development of colonic inflammation.Ovarian tumor deubiquitinase 1(OTUD1)is involved in immunoregulatory functions linked to infectious diseases.However,the effect of OTUD1 on intestinal immune responses during colonic inflammatory disorders such as inflammatory bowel disease(IBD)remains unclear.Here,we show that loss of OTUD1 in mice contributes to the pathogenesis of dextran sulfate sodium(DSS)-induced colitis via excessive release of proinflammatory cytokines.In addition,bone marrow transplantation experiments revealed that OTUD1 in hematopoietic cells plays a dominant role in protection against colitis.Mechanistically,OTUD1 physically interacts with receptor-interacting serine/threonine-protein kinase 1(RIPK1)and selectively cleaves K63-linked polyubiquitin chains from RIPK1 to inhibit the recruitment of NF-κB essential modulator(NEMO).Moreover,the expression of OTUD1 in mucosa samples from ulcerative colitis(UC)patients was lower than that in mucosa samples from healthy controls.Furthermore,we demonstrate that the UC-associated OTUD1 G430V mutation abolishes the ability of OTUD1 to inhibit RIPK1-mediated NF-κB activation and intestinal inflammation.Taken together,our study unveils a previously unexplored role of OTUD1 in moderating intestinal inflammation by inhibiting RIPK1-mediated NF-κB activation,suggesting that the OTUD1-RIPK1 axis could be a potential target for the treatment of IBD.