Inflammasomes are essential components of the innate immune system and its defense against infections,whereas the dysregulation of inflammasome activation has a detrimental effect on human health.The activation of inf...Inflammasomes are essential components of the innate immune system and its defense against infections,whereas the dysregulation of inflammasome activation has a detrimental effect on human health.The activation of inflammasomes is subjected to tight regulation to maintain immune homeostasis,yet the underlying mechanism remains elusive.Here,we identify USP3 as a direct deubiquitinating enzyme(DUB)for ASC,the central adapter mediating the assembly and activation of most inflammasomes.USP3 removes the K48-linked ubiquitination on ASC and strengthens its stability by blocking proteasomal degradation.Additionally,USP3 promotes inflammasome activation,and this function was confirmed in mouse models of aluminum(Alum)-induced peritonitis,F.novicida infection and flagellin-induced pneumonia in vivo.Our work unveils that USP3 functions as a key regulator of ASC ubiquitination and maintains the physiological role of ASC in mediating inflammasome activation,and we propose a new mechanism by which the ubiquitination of ASC regulates inflammasome activation.展开更多
The hypoxia-inducible factor(HIF)-mediated hypoxia signaling pathway influences oxygen homeostasis in aerobic organisms.This pathway is regulated by several other pathways.Elucidation of its regulation and the underly...The hypoxia-inducible factor(HIF)-mediated hypoxia signaling pathway influences oxygen homeostasis in aerobic organisms.This pathway is regulated by several other pathways.Elucidation of its regulation and the underlying mechanisms may provide insights into the strategies of adaptation and tolerance of organisms to hypoxia.In this study,we found that loss of ubiquitin-specific protease 3(usp3)in zebrafish promotes hypoxia tolerance.Zebrafish usp3 specifically binds to hif-1αa and induces its proteasomal degradation,which is dependent on its deubiquitinase activity.This process leads to the suppression of hypoxia signaling under hypoxia.In addition,usp3 catalyzes the deubiquitination of K63-polyubiquitinated hif-1αa.Endogenous evidence indicated that mammalian USP3 behaves like zebrafish usp3 in regulating the activity of HIF-1α.These findings revealed a novel role for usp3 in influencing hypoxia signaling and showed that usp3-mediated HIF-1αdegradation impairs hypoxia signaling,leading to a decrease in hypoxia tolerance.展开更多
Innate immunity provides immediate defense against viral infection. Influenza A virus(IAV) is able to get past the first line of defense. Elucidation of the molecular interaction between influenza factors and the newl...Innate immunity provides immediate defense against viral infection. Influenza A virus(IAV) is able to get past the first line of defense. Elucidation of the molecular interaction between influenza factors and the newly recognized host players in the innate response might help in our understanding of the root causes of virulence and pathogenicity of IAV. In this study, we show that expression of miR-26 a leads to a significant inhibition of IAV replication. miR-26 a does not directly target IAV genome. Instead, miR-26 a activates the type I interferon(IFN) signaling pathway and promotes the production of IFN-stimulated genes, thus suppressing viral replication. Furthermore,ubiquitin-specific protease 3(USP3), a negative regulator of type I IFN pathway, is targeted by miR-26 a upon IAV challenge. However, miR-26 a is significantly downregulated during IAV infection.Thus, downregulation of miR-26 a is a new strategy evolved by IAV to counteract cellular antiviral responses. Our findings indicate that delivery of miR-26 a may be a potential strategy for anti-IAV therapies.展开更多
基金This work was supported by grants from the National Key Research and Development Program(2021YFC2300603),the National Natural Science Foundation of China(32000633,31730026,81930039)the Natural Science Foundation of Shandong Province(ZR2020QH136)+1 种基金the China Postdoctoral Science Foundation(2020M682187)the Postdoctoral Innovation Project of Shandong Province(202002012).
文摘Inflammasomes are essential components of the innate immune system and its defense against infections,whereas the dysregulation of inflammasome activation has a detrimental effect on human health.The activation of inflammasomes is subjected to tight regulation to maintain immune homeostasis,yet the underlying mechanism remains elusive.Here,we identify USP3 as a direct deubiquitinating enzyme(DUB)for ASC,the central adapter mediating the assembly and activation of most inflammasomes.USP3 removes the K48-linked ubiquitination on ASC and strengthens its stability by blocking proteasomal degradation.Additionally,USP3 promotes inflammasome activation,and this function was confirmed in mouse models of aluminum(Alum)-induced peritonitis,F.novicida infection and flagellin-induced pneumonia in vivo.Our work unveils that USP3 functions as a key regulator of ASC ubiquitination and maintains the physiological role of ASC in mediating inflammasome activation,and we propose a new mechanism by which the ubiquitination of ASC regulates inflammasome activation.
基金NSFC[31721005 and 31830101 to W.X,31972786 to J.W.]The Strategic Priority Research Program of the Chinese Academy of Sciences[XDA24010308 to W.X.].
文摘The hypoxia-inducible factor(HIF)-mediated hypoxia signaling pathway influences oxygen homeostasis in aerobic organisms.This pathway is regulated by several other pathways.Elucidation of its regulation and the underlying mechanisms may provide insights into the strategies of adaptation and tolerance of organisms to hypoxia.In this study,we found that loss of ubiquitin-specific protease 3(usp3)in zebrafish promotes hypoxia tolerance.Zebrafish usp3 specifically binds to hif-1αa and induces its proteasomal degradation,which is dependent on its deubiquitinase activity.This process leads to the suppression of hypoxia signaling under hypoxia.In addition,usp3 catalyzes the deubiquitination of K63-polyubiquitinated hif-1αa.Endogenous evidence indicated that mammalian USP3 behaves like zebrafish usp3 in regulating the activity of HIF-1α.These findings revealed a novel role for usp3 in influencing hypoxia signaling and showed that usp3-mediated HIF-1αdegradation impairs hypoxia signaling,leading to a decrease in hypoxia tolerance.
基金supported by grants from the National Basic Research Program of China(973 Program,No.2012CB518900)the Beijing Natural Science Foundation(No.7122109)
文摘Innate immunity provides immediate defense against viral infection. Influenza A virus(IAV) is able to get past the first line of defense. Elucidation of the molecular interaction between influenza factors and the newly recognized host players in the innate response might help in our understanding of the root causes of virulence and pathogenicity of IAV. In this study, we show that expression of miR-26 a leads to a significant inhibition of IAV replication. miR-26 a does not directly target IAV genome. Instead, miR-26 a activates the type I interferon(IFN) signaling pathway and promotes the production of IFN-stimulated genes, thus suppressing viral replication. Furthermore,ubiquitin-specific protease 3(USP3), a negative regulator of type I IFN pathway, is targeted by miR-26 a upon IAV challenge. However, miR-26 a is significantly downregulated during IAV infection.Thus, downregulation of miR-26 a is a new strategy evolved by IAV to counteract cellular antiviral responses. Our findings indicate that delivery of miR-26 a may be a potential strategy for anti-IAV therapies.
