Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity,but the underlying molecular mechanisms remain incompletely understood.In this study,Sin1,a key component of mTOR complex 2(mTORC2...Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity,but the underlying molecular mechanisms remain incompletely understood.In this study,Sin1,a key component of mTOR complex 2(mTORC2),specifically regulates B cell growth and metabolism.Genetic ablation of Sin1 in B cells reduces the cell size at either the transitional stage or upon antigen stimulation and severely impairs metabolism.Sin1 deficiency also severely impairs B-cell proliferation,antibody responses,and anti-viral immunity.At the molecular level,Sin1 controls the expression and stability of the c-Myc protein and maintains the activity of mTORC1 through the Akt-dependent inactivation of GSK3 and TSC1/2,respectively.Therefore,our study reveals a novel and specific role for Sin1 in coordinating the activation of mTORC2 and mTORC1 to control B cell growth and metabolism.展开更多
Mammalian target of rapamycin complex 2(mTORC2)is a key downstream mediator of phosphoinositol-3-kinase(PI3K)dependent growth factor signaling.In lymphocytes,mTORC2 has emerged as an important regulator of cell develo...Mammalian target of rapamycin complex 2(mTORC2)is a key downstream mediator of phosphoinositol-3-kinase(PI3K)dependent growth factor signaling.In lymphocytes,mTORC2 has emerged as an important regulator of cell development,homeostasis and immune responses.However,our current understanding of mTORC2 functions and the molecular mechanisms regulating mTORC2 signaling in B and T cells are still largely incomplete.Recent studies have begun to shed light on this important pathway.We have previously reported that mTORC2 mediates growth factor dependent phosphorylation of Akt and facilitates Akt dependent phosphorylation and inactivation of transcription factors FoxO1 and FoxO3a.We have recently explored the functions of mTORC2 in B cells and show that mTORC2 plays a key role in regulating survival and immunoglobulin(Ig)gene recombination of bone marrow B cells through an Akt2-FoxO1 dependent mechanism.Ig recombination is suppressed in proliferating B cells to ensure that DNA double strand breaks are not generated in actively dividing cells.Our results raise the possibility that genetic or pharmacologic inhibition of mTORC2 may promote B cell tumor development as a result of inefficient suppression of Ig recombination in dividing B cells.We also propose a novel strategy to treat cancers based on our recent discovery that mTORC2 regulates Akt protein stability.展开更多
基金This study was partially supported by grant PR093728(DoD to B.S.)the National Natural Science Foundation of China(grant numbers 31470845 and 81430033 to B.S.,31422020 to F.L.and 31600704 to H.H.Z.)+2 种基金grant 13JC1404700 from the Program of Science and Technology Commission of Shanghai Municipality(B.S.)the Ministry of Science and Technology of China(Program 2014CB943600,F.L.)Chinese Mega Project on Infectious Diseases(No.2018ZX10302301).
文摘Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity,but the underlying molecular mechanisms remain incompletely understood.In this study,Sin1,a key component of mTOR complex 2(mTORC2),specifically regulates B cell growth and metabolism.Genetic ablation of Sin1 in B cells reduces the cell size at either the transitional stage or upon antigen stimulation and severely impairs metabolism.Sin1 deficiency also severely impairs B-cell proliferation,antibody responses,and anti-viral immunity.At the molecular level,Sin1 controls the expression and stability of the c-Myc protein and maintains the activity of mTORC1 through the Akt-dependent inactivation of GSK3 and TSC1/2,respectively.Therefore,our study reveals a novel and specific role for Sin1 in coordinating the activation of mTORC2 and mTORC1 to control B cell growth and metabolism.
基金supported in part by grant AI 063348(NIH)and PR093728(DOD)(to B.S.).
文摘Mammalian target of rapamycin complex 2(mTORC2)is a key downstream mediator of phosphoinositol-3-kinase(PI3K)dependent growth factor signaling.In lymphocytes,mTORC2 has emerged as an important regulator of cell development,homeostasis and immune responses.However,our current understanding of mTORC2 functions and the molecular mechanisms regulating mTORC2 signaling in B and T cells are still largely incomplete.Recent studies have begun to shed light on this important pathway.We have previously reported that mTORC2 mediates growth factor dependent phosphorylation of Akt and facilitates Akt dependent phosphorylation and inactivation of transcription factors FoxO1 and FoxO3a.We have recently explored the functions of mTORC2 in B cells and show that mTORC2 plays a key role in regulating survival and immunoglobulin(Ig)gene recombination of bone marrow B cells through an Akt2-FoxO1 dependent mechanism.Ig recombination is suppressed in proliferating B cells to ensure that DNA double strand breaks are not generated in actively dividing cells.Our results raise the possibility that genetic or pharmacologic inhibition of mTORC2 may promote B cell tumor development as a result of inefficient suppression of Ig recombination in dividing B cells.We also propose a novel strategy to treat cancers based on our recent discovery that mTORC2 regulates Akt protein stability.
