GRK6 maintains hematopoietic stem cell self-renewal through ROS homeostasis

【作者】 刘操； 乐秋旻； 姚文青； 颜彪； 袁曼； 陈跃军； 马兰；

【机构】 复旦大学药理研究中心；

【摘要】 G-protein-coupled receptor kinases(GRKs)’s canonical function is to initiate the homologous desensitization of stimulated receptors and thus act as crucial negative regulators of G protein-coupled receptors(GPCRs).Recently,novel roles of GRKs in cell cycle regulation and neurogenesis were discovered.Here,we found GRK6 also played vital roles in hematopoiesis.GRK6 ablation led to pronounced lymphocytopenia in both T and B cells,which was due to loss of the hematopoietic stem cells(HSCs),common multiple progenitor cells(CLPs),and concomitant impairment of HSC self-renewal and differentiation.The above phenotype of GRK6-related functional defect was reactive oxygen species(ROS)related.Antioxidant NAC treatment further decreased HSC and CLP populations and more severe lymphoid defect.On the contrary,a mild dose of hydrogen peroxide(H2O2)could transiently rescue the decrease in cell numbers of HSC and CLP.Analysis of HSCs and common lymphoid progenitors by RNA sequencing indicates that GRK6 possibly participate in stress-related pathways,which is consistent with disturbed ROS response.Our work first demonstrates previously unrecognized physiological importance of GRK6 in regulating HSC renewal and indentifies its possible mechanism by regulating ROS homeostasis.Proofs regarding GRKs participating in ROS homeostasis provide basis for further exploring the molecular mechanisms of GRK in hematopoiesis.更多还原

【Abstract】 G-protein-coupled receptor kinases(GRKs)’s canonical function is to initiate the homologous desensitization of stimulated receptors and thus act as crucial negative regulators of G protein-coupled receptors(GPCRs).Recently,novel roles of GRKs in cell cycle regulation and neurogenesis were discovered.Here,we found GRK6 also played vital roles in hematopoiesis.GRK6 ablation led to pronounced lymphocytopenia in both T and B cells,which was due to loss of the hematopoietic stem cells(HSCs),common multiple progenitor cells(CLPs),and concomitant impairment of HSC self-renewal and differentiation.The above phenotype of GRK6-related functional defect was reactive oxygen species(ROS) related.Antioxidant NAC treatment further decreased HSC and CLP populations and more severe lymphoid defect.On the contrary,a mild dose of hydrogen peroxide(H2O2) could transiently rescue the decrease in cell numbers of HSC and CLP.Analysis of HSCs and common lymphoid progenitors by RNA sequencing indicates that GRK6 possibly participate in stress-related pathways,which is consistent with disturbed ROS response.Our work first demonstrates previously unrecognized physiological importance of GRK6 in regulating HSC renewal and indentifies its possible mechanism by regulating ROS homeostasis.Proofs regarding GRKs participating in ROS homeostasis provide basis for further exploring the molecular mechanisms of GRK in hematopoiesis.更多还原