The cGAS-STING pathway plays a crucial role in the innate immune system by detecting mislocalized double-stranded DNA(dsDNA)in the cytoplasm and triggering downstream signal transduction.Understanding the mechanisms b...The cGAS-STING pathway plays a crucial role in the innate immune system by detecting mislocalized double-stranded DNA(dsDNA)in the cytoplasm and triggering downstream signal transduction.Understanding the mechanisms by which cGAS and STING operate is vital for gaining insights into the biology of this pathway.This review provides a detailed examination of the structural features of cGAS and STING proteins,with a particular emphasis on their activation and inhibition mechanisms.We also discuss the novel discovery of STING functioning as an ion channel.Furthermore,we offer an overview of key agonists and antagonists of cGAS and STING,shedding light on their mechanisms of action.Deciphering the molecular intricacies of the cGAS-STING pathway holds significant promise for the development of targeted therapies aimed at maintaining immune homeostasis within both innate and adaptive immunity.展开更多
Receptor tyrosine kinases couple a wide variety of extracellular cues to cellular responses.The class III subfamily comprises the platelet-derived growth factor receptor,c-Kit,Flt3 and c-Fms,all of which relay cell pr...Receptor tyrosine kinases couple a wide variety of extracellular cues to cellular responses.The class III subfamily comprises the platelet-derived growth factor receptor,c-Kit,Flt3 and c-Fms,all of which relay cell proliferation signals upon ligand binding.Accordingly,mutations in these proteins that confer ligand-independent activation are found in a subset of cancers.These mutations cluster in the juxtamembrane(JM)and catalytic tyrosine kinase domain(TKD)regions.In the case of acute myeloid leukemia(AML),the juxtamembrane(named ITD for internal tandem duplication)and TKD Flt3 mutants differ in their spectra of clinical outcomes.Although the mechanism of aberrant activation has been largely elucidated by biochemical and structural analyses of mutant kinases,the differences in disease presentation cannot be attributed to a change in substrate specificity or signaling strength of the catalytic domain.This review discusses the latest literature and presents a working model of differential Flt3 signaling based on mis-localized juxtamembrane autophosphorylation,to account for the disease variation.This will have bearing on therapeutic approaches in a complex disease such as AML,for which no efficacious drug yet exists.展开更多
Excess phosphate(Pi)is stored into the vacuole through Pi transporters so that cytoplasmic Pi levels remain stable in plant cells.We hypothesized that the vacuolar Pi transporters may harbor a Pi-sensing mechanism so ...Excess phosphate(Pi)is stored into the vacuole through Pi transporters so that cytoplasmic Pi levels remain stable in plant cells.We hypothesized that the vacuolar Pi transporters may harbor a Pi-sensing mechanism so that they are activated to deliver Pi into the vacuole only when cytosolic Pi reaches a threshold high level.We tested this hypothesis using Vacuolar Phosphate Transporter 1(VPT1),a SPX domain-containing vacuolar Pi transporter,as a model.Recent studies have defined SPX as a Pi-sensing module that binds inositol polyphosphate signaling molecules(InsPs)produced at high cellular Pi status.We showed here that Pi-deficient conditions or mutation of the SPX domain severely impaired the transport activity of VPT1.We further identified an auto-inhibitory domain in VPT1 that suppresses its transport activity.Taking together the results from detailed structure-function analyses,our study suggests that VPT1 is in the auto-inhibitory state when Pi status is low,whereas at high cellular Pi status InsPs are produced and bind SPX domain to switch on VPT1 activity to deliver Pi into the vacuole.This thus provides an auto-regulatory mechanism for VPT1-mediated Pi sensing and homeostasis in plant cells.展开更多
基金supported by grants from the National Key R&D Program of China(2021YFC2301400)the National Natural Science Foundation of China(32070876,82071155,82271023 and 82301052)the Shanxi Provincial Science Fund for Distinguished Young Scholars program(202103021221001 and 202303021223007).
文摘The cGAS-STING pathway plays a crucial role in the innate immune system by detecting mislocalized double-stranded DNA(dsDNA)in the cytoplasm and triggering downstream signal transduction.Understanding the mechanisms by which cGAS and STING operate is vital for gaining insights into the biology of this pathway.This review provides a detailed examination of the structural features of cGAS and STING proteins,with a particular emphasis on their activation and inhibition mechanisms.We also discuss the novel discovery of STING functioning as an ion channel.Furthermore,we offer an overview of key agonists and antagonists of cGAS and STING,shedding light on their mechanisms of action.Deciphering the molecular intricacies of the cGAS-STING pathway holds significant promise for the development of targeted therapies aimed at maintaining immune homeostasis within both innate and adaptive immunity.
文摘Receptor tyrosine kinases couple a wide variety of extracellular cues to cellular responses.The class III subfamily comprises the platelet-derived growth factor receptor,c-Kit,Flt3 and c-Fms,all of which relay cell proliferation signals upon ligand binding.Accordingly,mutations in these proteins that confer ligand-independent activation are found in a subset of cancers.These mutations cluster in the juxtamembrane(JM)and catalytic tyrosine kinase domain(TKD)regions.In the case of acute myeloid leukemia(AML),the juxtamembrane(named ITD for internal tandem duplication)and TKD Flt3 mutants differ in their spectra of clinical outcomes.Although the mechanism of aberrant activation has been largely elucidated by biochemical and structural analyses of mutant kinases,the differences in disease presentation cannot be attributed to a change in substrate specificity or signaling strength of the catalytic domain.This review discusses the latest literature and presents a working model of differential Flt3 signaling based on mis-localized juxtamembrane autophosphorylation,to account for the disease variation.This will have bearing on therapeutic approaches in a complex disease such as AML,for which no efficacious drug yet exists.
基金the China Postdoctoral Science Foundation 2020M683537(to M.L)National Natural Science Foundation of China 32200216(to M.L)the National Science Foundation MCB 2041585(to S.L).
文摘Excess phosphate(Pi)is stored into the vacuole through Pi transporters so that cytoplasmic Pi levels remain stable in plant cells.We hypothesized that the vacuolar Pi transporters may harbor a Pi-sensing mechanism so that they are activated to deliver Pi into the vacuole only when cytosolic Pi reaches a threshold high level.We tested this hypothesis using Vacuolar Phosphate Transporter 1(VPT1),a SPX domain-containing vacuolar Pi transporter,as a model.Recent studies have defined SPX as a Pi-sensing module that binds inositol polyphosphate signaling molecules(InsPs)produced at high cellular Pi status.We showed here that Pi-deficient conditions or mutation of the SPX domain severely impaired the transport activity of VPT1.We further identified an auto-inhibitory domain in VPT1 that suppresses its transport activity.Taking together the results from detailed structure-function analyses,our study suggests that VPT1 is in the auto-inhibitory state when Pi status is low,whereas at high cellular Pi status InsPs are produced and bind SPX domain to switch on VPT1 activity to deliver Pi into the vacuole.This thus provides an auto-regulatory mechanism for VPT1-mediated Pi sensing and homeostasis in plant cells.
