Radiotherapy induces DNA damage,resulting in cell cycle arrest and activation of cell-intrinsic death pathways.However,the radioresistance of some tumour entities such as malignant melanoma limits its clinical applica...Radiotherapy induces DNA damage,resulting in cell cycle arrest and activation of cell-intrinsic death pathways.However,the radioresistance of some tumour entities such as malignant melanoma limits its clinical application.The innate immune sensing receptor retinoic acid-inducible gene I(RIG-I)is ubiquitously expressed and upon activation triggers an immunogenic form of cell death in a variety of tumour cell types including melanoma.To date,the potential of RIG-I ligands to overcome radioresistance of tumour cells has not been investigated.Here,we demonstrate that RIG-I activation enhanced the extent and immunogenicity of irradiation-induced tumour cell death in human and murine melanoma cells in vitro and improved survival in the murine B16 melanoma model in vivo.Transcriptome analysis pointed to a central role for p53,which was confirmed using p53^(-/-)B16 cells.In vivo,the additional effect of RIG-I in combination with irradiation on tumour growth was absent in mice carrying p53^(-/-)B16 tumours,while the antitumoural response to RIG-I stimulation alone was maintained.Our results identify p53 as a pivotal checkpoint that is triggered by RIG-I resulting in enhanced irradiation-induced tumour cell death.Thus,the combined administration of RIG-I ligands and radiotherapy is a promising approach to treating radioresistant tumours with a functional p53 pathway,such as melanoma.展开更多
In their recently published study in Nature,Jenson et al.1 provide compelling,unexpected evidence that bacterial cGAMP synthase(cGAS)and other cGAS/DncV-like Nucleotidyltransferases(CD-NTase)undergo ubiquitin-like con...In their recently published study in Nature,Jenson et al.1 provide compelling,unexpected evidence that bacterial cGAMP synthase(cGAS)and other cGAS/DncV-like Nucleotidyltransferases(CD-NTase)undergo ubiquitin-like conjugation(ULC)in type-II cyclic-oligonucleotide-based anti-phage signaling systems(CBASS).cGAS conjugation promotes cyclic-nucleotide(CN)formation and thus antiphage defense.Furthermore,the authors also reveal a new class of phage-encoded CBASS inhibitor,T4 Vs.4,a CN-sponge which limits CBASS effector function and promotes phage replication,revealing another weapon in the“arms race”between phages and their bacterial hosts.展开更多
In their recently published study in Science,Li et al.1 unravel how hyperphosphorylation and chromatin-tethering of the double-stranded(dsDNA)sensor cGAMP synthase(cGAS)prevent self DNA recognition during mitosis(Fig....In their recently published study in Science,Li et al.1 unravel how hyperphosphorylation and chromatin-tethering of the double-stranded(dsDNA)sensor cGAMP synthase(cGAS)prevent self DNA recognition during mitosis(Fig.1);providing important insight into how this innate immune sensor balances its essential function for pathogen defense against potential autoinflammation.展开更多
基金funded by Deutsche Forschungsgemeinschaft(DFG,GermanResearch Foundation)under Germany's Excellence Strategy EXC2151390873048 of which E.B.,G.H.,and M.S.are memberssupported by other grants of DFG,including Project-ID 369799452 TRR237 to E.B.,G.H.,and M.S.,Project-ID 397484323 TRR259 to G.H.,GRK 2168 to E.B.and M.S.,and DFG SCHL1930/1-2+1 种基金funded by the Deutsche Krebshilfe through a Mildred Scheel Nachwuchszentrum(70113307)the recipient of a PhD scholarship from Bayer Pharma AG(40860128).
文摘Radiotherapy induces DNA damage,resulting in cell cycle arrest and activation of cell-intrinsic death pathways.However,the radioresistance of some tumour entities such as malignant melanoma limits its clinical application.The innate immune sensing receptor retinoic acid-inducible gene I(RIG-I)is ubiquitously expressed and upon activation triggers an immunogenic form of cell death in a variety of tumour cell types including melanoma.To date,the potential of RIG-I ligands to overcome radioresistance of tumour cells has not been investigated.Here,we demonstrate that RIG-I activation enhanced the extent and immunogenicity of irradiation-induced tumour cell death in human and murine melanoma cells in vitro and improved survival in the murine B16 melanoma model in vivo.Transcriptome analysis pointed to a central role for p53,which was confirmed using p53^(-/-)B16 cells.In vivo,the additional effect of RIG-I in combination with irradiation on tumour growth was absent in mice carrying p53^(-/-)B16 tumours,while the antitumoural response to RIG-I stimulation alone was maintained.Our results identify p53 as a pivotal checkpoint that is triggered by RIG-I resulting in enhanced irradiation-induced tumour cell death.Thus,the combined administration of RIG-I ligands and radiotherapy is a promising approach to treating radioresistant tumours with a functional p53 pathway,such as melanoma.
文摘In their recently published study in Nature,Jenson et al.1 provide compelling,unexpected evidence that bacterial cGAMP synthase(cGAS)and other cGAS/DncV-like Nucleotidyltransferases(CD-NTase)undergo ubiquitin-like conjugation(ULC)in type-II cyclic-oligonucleotide-based anti-phage signaling systems(CBASS).cGAS conjugation promotes cyclic-nucleotide(CN)formation and thus antiphage defense.Furthermore,the authors also reveal a new class of phage-encoded CBASS inhibitor,T4 Vs.4,a CN-sponge which limits CBASS effector function and promotes phage replication,revealing another weapon in the“arms race”between phages and their bacterial hosts.
基金This work is supported by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)under German's Excellence Strategy-EXC2151_390873048 of which EB and MS are members.
文摘In their recently published study in Science,Li et al.1 unravel how hyperphosphorylation and chromatin-tethering of the double-stranded(dsDNA)sensor cGAMP synthase(cGAS)prevent self DNA recognition during mitosis(Fig.1);providing important insight into how this innate immune sensor balances its essential function for pathogen defense against potential autoinflammation.
