生命学院学术报告

Title：Innate Immune Sensing and Signaling of Cytosolic DNA

Speaker: Pu Gao

Research Associate

Structural Biology Program

Memorial Sloan-Kettering Cancer Center

Time: 14:30-15:30 PM, May 29, 2015 (Fri.)

Venue: Rm. 411, New Life Sciences Building

The appearance of DNA in the cytoplasm is a very dangerous signal to cells. This could be caused by viral or bacterial infection, or as a result of cellular damage that leaks host DNA into the cytoplasm. Cytosolic DNA activates the host immune response, which is critically dependent on the newly identified cGAS-cGAMP-STING pathway. Our structure-function studies have demonstrated that upon DNA binding, cGAS is activated through conformational transitions, resulting in formation of a catalytically competent and accessible nucleotide-binding pocket for generation of 2’3’-cGAMP. Further, cyclization occurs in a stepwise manner through initial generation of 5’-pppG(2’,5’)A prior to cyclization to 2’3’-cGAMP, with the latter positioned precisely in the catalytic pocket. These studies established 2’3’-cGAMP as a founding member of a family of metazoan 2’,5’-containing cyclic heteronucleotide second messengers distinct from bacterial 3’,5’ cyclic dinucleotides. Follow-up structure-function studies from our laboratory have shown that human and mouse STING undergo an ‘open’ to ‘closed’ conformational transition upon binding 2’3’-cGAMP and its linkage isomers. Comparing hSTING to mSTING in cellular assays, 2’,5’-linkage-containing cGAMP isomers were more specific triggers of the IFN pathway compared to the all 3’,5’-linkage isomer counterparts. In the drug design aspect, our results highlight the critical role of the lid residue at position 230 (Gly in hSTING; Ile in mSTING) for the species selectivity of an anticancer drug DMXAA, which shows promising anticancer activity in mouse models but has no effect on humans. Our structural and functional results also shed light on strategies to restore an efficient DMXAA-response of hSTING based on the binding pocket S162A and Q266I substitutions.

Welcome!