T-cell immunoglobulin mucin family member-1(TIM-1,also known as HAVCR1/KIM-1)is a transmembrane glycoprotein that has been reported to act as an entry receptor for multiple flaviviruses including Zika virus(ZIKV).The ...T-cell immunoglobulin mucin family member-1(TIM-1,also known as HAVCR1/KIM-1)is a transmembrane glycoprotein that has been reported to act as an entry receptor for multiple flaviviruses including Zika virus(ZIKV).The post-translational regulation of TIM-1 and its effects on ZIKV infection are unclear.In this study,we identified the membrane-associated RING-CH-type finger(MARCH)E3 ubiquitin ligase family members MARCH2 and MARCH3 as critical negative regulators of TIM-1 under physiological conditions.MARCH2 and MARCH3 associate with TIM-1 and mediate its K48-linked polyubiquitination at K338 and K346 respectively,leading to subsequent proteasomal degradation.While deficiency of either MARCH2 or MARCH3 modestly increases TIM-1 levels and enhances ZIKV infectivity,double knockout of MARCH2/3 has a more dramatic effect.Double knockout of MARCH2/3 increased ZIKV infectivity in wild-type but not TIM-1 knockout cells,and reconstitution of TIM-1^(K338R/K346R) into TIM-1-deficient cells increases ZIKV infectivity to a higher degree than reconstitution with wild-type TIM-1.Knockout of either MARCH2 or MARCH3 increased ZIKV infectivity and pathogenesis in mice,whereas double knockout of MARCH2/3 has a more dramatic effect.These findings suggest that MARCH2 and MARCH3 target TIM-1 for K48-linked polyubiquitination and proteasomal degradation,thereby acting as redundant host restriction factors to limit ZIKV infection and pathogenesis.展开更多
The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis(IAC).How this axis is regulated to modulate IAC remains unknown.Here,we show that the plasma membrane-associated E3 ubiquitin ligase...The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis(IAC).How this axis is regulated to modulate IAC remains unknown.Here,we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates STAT3 activation triggered by IL-6,as well as another IL-6 subfamily member,Oncostatin M(OSM).MARCH3 is associated with the IL-6 receptorα-chain(IL-6Rα)and its coreceptor gp130.Biochemical experiments indicated that MARCH3 mediates the polyubiquitination of IL-6Rαat K401 and gp130 at K849 following IL-6 stimulation,leading to their translocation to and degradation in lysosomes.MARCH3 deficiency increases IL-6-and OSM-triggered activation of STAT3 and induction of downstream effector genes in various cell types.MARCH3 deficiency enhances dextran sulfate sodium(DSS)-induced STAT3 activation,increases the expression of inflammatory cytokines,and exacerbates colitis,as well as azoxymethane(AOM)/DSS-induced colitis-associated cancer in mice.In addition,MARCH3 is downregulated in human colorectal cancer tissues and associated with poor survival across different cancer types.Our findings suggest that MARCH3 is a pivotal negative regulator of IL-6-induced STAT3 activation,inflammation,and inflammation-associated carcinogenesis.展开更多
Interleukin 5(IL-5)plays crucial roles in type 2-high asthma by mediating eosinophil maturation,activation,chemotaxis and survival.Inhibition of IL-5 signaling is considered a strategy for asthma treatment.Here,we ide...Interleukin 5(IL-5)plays crucial roles in type 2-high asthma by mediating eosinophil maturation,activation,chemotaxis and survival.Inhibition of IL-5 signaling is considered a strategy for asthma treatment.Here,we identified MARCH2 and MARCH3 as critical negative regulators of IL-5-triggered signaling.MARCH2 and MARCH3 associate with the IL-5 receptorαchain(IL-5Rα)and mediate its K27-linked polyubiquitination at K379 and K383,respectively,and its subsequent lysosomal degradation.Deficiency of MARCH2 or MARCH3 modestly increases the level of IL-5Rαand enhances IL-5-induced signaling,whereas double knockout of MARCH2/3 has a more dramatic effect.March2/3 double knockout markedly increases the proportions of eosinophils in the bone marrow and peripheral blood in mice.Double knockout of March2/3 aggravates ovalbumin(OVA)-induced eosinophilia and causes increased inflammatory cell infiltration,peribronchial mucus secretion and production of Th2 cytokines.Neutralization of Il-5 attenuates OVA-induced airway inflammation and the enhanced effects of March2/3 double deficiency.These findings suggest that MARCH2 and MARCH3 play redundant roles in targeting IL-5Rαfor degradation and negatively regulating allergic airway inflammation.展开更多
基金supported by grants from the State Key R&D Program of China(2024YFA1306500,2022YFA1304900)the National Natural Science Foundation of China(32188101)+2 种基金the Major Project of Guangzhou National Laboratory(GZNL2024A01014,GZNL2024A01016)the Fundamental Research Funds for the Central Universities(2042022dx0003)Natural Science Foundation of Wuhan(2024040701010031).
文摘T-cell immunoglobulin mucin family member-1(TIM-1,also known as HAVCR1/KIM-1)is a transmembrane glycoprotein that has been reported to act as an entry receptor for multiple flaviviruses including Zika virus(ZIKV).The post-translational regulation of TIM-1 and its effects on ZIKV infection are unclear.In this study,we identified the membrane-associated RING-CH-type finger(MARCH)E3 ubiquitin ligase family members MARCH2 and MARCH3 as critical negative regulators of TIM-1 under physiological conditions.MARCH2 and MARCH3 associate with TIM-1 and mediate its K48-linked polyubiquitination at K338 and K346 respectively,leading to subsequent proteasomal degradation.While deficiency of either MARCH2 or MARCH3 modestly increases TIM-1 levels and enhances ZIKV infectivity,double knockout of MARCH2/3 has a more dramatic effect.Double knockout of MARCH2/3 increased ZIKV infectivity in wild-type but not TIM-1 knockout cells,and reconstitution of TIM-1^(K338R/K346R) into TIM-1-deficient cells increases ZIKV infectivity to a higher degree than reconstitution with wild-type TIM-1.Knockout of either MARCH2 or MARCH3 increased ZIKV infectivity and pathogenesis in mice,whereas double knockout of MARCH2/3 has a more dramatic effect.These findings suggest that MARCH2 and MARCH3 target TIM-1 for K48-linked polyubiquitination and proteasomal degradation,thereby acting as redundant host restriction factors to limit ZIKV infection and pathogenesis.
基金This work was supported by grants from the National Key R&D Program of China(2017YFA0505800)the National Natural Science Foundation of China(31630045,31830024,31900556,and 32070775)+2 种基金the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071)the National Postdoctoral Program for Innovative Talents(BX20190255)the China Postdoctoral Science Foundation(2019M662706).
文摘The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis(IAC).How this axis is regulated to modulate IAC remains unknown.Here,we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates STAT3 activation triggered by IL-6,as well as another IL-6 subfamily member,Oncostatin M(OSM).MARCH3 is associated with the IL-6 receptorα-chain(IL-6Rα)and its coreceptor gp130.Biochemical experiments indicated that MARCH3 mediates the polyubiquitination of IL-6Rαat K401 and gp130 at K849 following IL-6 stimulation,leading to their translocation to and degradation in lysosomes.MARCH3 deficiency increases IL-6-and OSM-triggered activation of STAT3 and induction of downstream effector genes in various cell types.MARCH3 deficiency enhances dextran sulfate sodium(DSS)-induced STAT3 activation,increases the expression of inflammatory cytokines,and exacerbates colitis,as well as azoxymethane(AOM)/DSS-induced colitis-associated cancer in mice.In addition,MARCH3 is downregulated in human colorectal cancer tissues and associated with poor survival across different cancer types.Our findings suggest that MARCH3 is a pivotal negative regulator of IL-6-induced STAT3 activation,inflammation,and inflammation-associated carcinogenesis.
基金This work was supported by grants from the National Natural Science Foundation of China(32188101,31830024 and 32070775)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071)the Fundamental Research Funds for the Central Universities.
文摘Interleukin 5(IL-5)plays crucial roles in type 2-high asthma by mediating eosinophil maturation,activation,chemotaxis and survival.Inhibition of IL-5 signaling is considered a strategy for asthma treatment.Here,we identified MARCH2 and MARCH3 as critical negative regulators of IL-5-triggered signaling.MARCH2 and MARCH3 associate with the IL-5 receptorαchain(IL-5Rα)and mediate its K27-linked polyubiquitination at K379 and K383,respectively,and its subsequent lysosomal degradation.Deficiency of MARCH2 or MARCH3 modestly increases the level of IL-5Rαand enhances IL-5-induced signaling,whereas double knockout of MARCH2/3 has a more dramatic effect.March2/3 double knockout markedly increases the proportions of eosinophils in the bone marrow and peripheral blood in mice.Double knockout of March2/3 aggravates ovalbumin(OVA)-induced eosinophilia and causes increased inflammatory cell infiltration,peribronchial mucus secretion and production of Th2 cytokines.Neutralization of Il-5 attenuates OVA-induced airway inflammation and the enhanced effects of March2/3 double deficiency.These findings suggest that MARCH2 and MARCH3 play redundant roles in targeting IL-5Rαfor degradation and negatively regulating allergic airway inflammation.
