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Rat and human STINGs profile similarly towards anticancer/antiviral compounds.

Authors: Zhang, H  Han, MJ  Tao, J  Ye, ZY  Du, XX  Deng, MJ  Zhang, XY  Li, LF  Jiang, ZF  Su, XD 
Citation: Zhang H, etal., Sci Rep. 2015 Dec 16;5:18035. doi: 10.1038/srep18035.
Pubmed: (View Article at PubMed) PMID:26669264
DOI: Full-text: DOI:10.1038/srep18035

Cyclic dinucleotides (CDNs) and antitumor/antiviral agents (DMXAA and CMA) trigger STING-dependent innate immunity activation. Accumulative evidences have showed that DMXAA and CMA selectively activate mouse, but not human STING signaling. The mechanism underlying this species selectivity remains poorly understood. In this report, we have shown that human and rat STINGs display more similar signaling profiles toward DMXAA and CMA than that of human and mouse STINGs, suggesting that rat is more suitable for preclinical testing of STING-targeted drugs. We have also determined the crystal structures of both apo rat STING and its complex with cyclic GMP-AMP with 2'5' and 3'5' phosphodiester linkage (2'3'-cGAMP), a human endogenous CDN. Structure-guided biochemical analysis also revealed the functional importance of the connecting loop (A140-N152) between membrane and cytosolic domains in STING activation. Taken together, these findings reveal that rat STING is more closely related to human STING in terms of substrate preference, serving as a foundation for the development of STING-targeted drugs.

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CRRD Object Information
CRRD ID: 11344949
Created: 2016-07-09
Species: All species
Last Modified: 2016-07-09
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.