Abstract |
Agonists of mouse STING (TMEM173) shrink and even cure solid tumors by activating innate immunity; human STING (hSTING) agonists are needed to test this therapeutic hypothesis in humans. The endogenous STING agonist is 2'3'-cGAMP, a second messenger that signals the presence of cytosolic double-stranded DNA. We report activity-guided partial purification and identification of ecto- nucleotide pyrophosphatase/ phosphodiesterase (ENPP1) to be the dominant 2'3'-cGAMP hydrolyzing activity in cultured cells. The hydrolysis activity of ENPP1 was confirmed using recombinant protein and was depleted in tissue extracts and plasma from Enpp1(-/-) mice. We synthesized a hydrolysis-resistant bisphosphothioate analog of 2'3'-cGAMP (2'3'-cG(s)A(s)MP) that has similar affinity for hSTING in vitro and is ten times more potent at inducing IFN-β secretion from human THP1 monocytes. Studies in mouse Enpp1(-/-) lung fibroblasts indicate that resistance to hydrolysis contributes substantially to its higher potency. 2'3'-cG(s)A(s)MP is therefore improved over natural 2'3'-cGAMP as a model agonist and has potential as a vaccine adjuvant and cancer therapeutic.
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Authors | Lingyin Li, Qian Yin, Pia Kuss, Zoltan Maliga, José L Millán, Hao Wu, Timothy J Mitchison |
Journal | Nature chemical biology
(Nat Chem Biol)
Vol. 10
Issue 12
Pg. 1043-8
(Dec 2014)
ISSN: 1552-4469 [Electronic] United States |
PMID | 25344812
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Membrane Proteins
- Nucleotides, Cyclic
- Organothiophosphorus Compounds
- Recombinant Proteins
- STING1 protein, human
- Sting1 protein, mouse
- cyclic guanosine monophosphate-adenosine monophosphate
- Interferon-beta
- Phosphoric Diester Hydrolases
- ectonucleotide pyrophosphatase phosphodiesterase 1
- Pyrophosphatases
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Topics |
- Animals
- Antineoplastic Agents
(chemical synthesis, pharmacology)
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic
- Humans
- Hydrolysis
- Interferon-beta
- Membrane Proteins
(agonists, deficiency, genetics, metabolism)
- Mice
- Monocytes
(drug effects, metabolism, pathology)
- Nucleotides, Cyclic
(chemistry, metabolism, pharmacology)
- Organothiophosphorus Compounds
(chemical synthesis, pharmacology)
- Phosphoric Diester Hydrolases
(genetics, metabolism)
- Pyrophosphatases
(antagonists & inhibitors, genetics, metabolism)
- Recombinant Proteins
(genetics, metabolism)
- Second Messenger Systems
(genetics)
- Signal Transduction
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