Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint
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Published on: January 20, 2023
Rachel Mardjuki1, Songnan Wang2, Jacqueline Carozza3
1Department of Biochemistry, Stanford University, Stanford, CA 94305, USA; ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Arc Institute, Palo Alto, CA 94304, USA; Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
Abstract:
2'3'-Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) is a second messenger synthesized upon detection of cytosolic double-stranded DNA (dsDNA) and passed between cells to facilitate downstream immune signaling. Ectonucleotide pyrophosphatase phosphodiesterase I (ENPP1), an extracellular enzyme, was the only metazoan hydrolase known to regulate cGAMP levels to dampen anti-cancer immunity. Here, we uncover ENPP3 as the second and likely the only other metazoan cGAMP hydrolase under homeostatic conditions. ENPP3 has a tissue expression pattern distinct from ENPP1's and accounts for all cGAMP hydrolysis activity in ENPP1-deficient mice. Importantly, we also show that, as with ENPP1, selectively abolishing ENPP3's cGAMP hydrolysis activity results in diminished cancer growth and metastasis of certain tumor types in a stimulator of interferon genes (STING)-dependent manner. Both ENPP1 and ENPP3 are extracellular enzymes, suggesting the dominant role that extracellular cGAMP must play as a mediator of cell-cell innate immune communication. Our work demonstrates that ENPP1 and ENPP3 non-redundantly dampen extracellular cGAMP-STING signaling, pointing to ENPP3 as a target for cancer immunotherapy.
Insights
Researchers identified ENPP3 as a second enzyme that breaks down cyclic GMP-AMP (cGAMP), a molecule involved in immune signaling. Inhibiting ENPP3 reduces cancer growth, suggesting it as a new immunotherapy target.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- Cyclic GMP-AMP (cGAMP) is a second messenger crucial for immune signaling upon detecting cytosolic double-stranded DNA (dsDNA).
- Ectonucleotide pyrophosphatase phosphodiesterase I (ENPP1) was the sole known metazoan enzyme regulating cGAMP to suppress anti-cancer immunity.
Purpose of the Study:
- To identify additional metazoan enzymes that hydrolyze cGAMP.
- To investigate the role of ENPP3 in cGAMP hydrolysis and its impact on cancer immunity.
Main Methods:
- Enzyme activity assays to measure cGAMP hydrolysis.
- Analysis of ENPP3 tissue expression patterns.
- Assessment of cancer growth and metastasis in ENPP1-deficient and ENPP3-manipulated mouse models.
- STING-dependent signaling pathway analysis.
Main Results:
- ENPP3 was identified as the second metazoan enzyme, besides ENPP1, that hydrolyzes cGAMP under homeostatic conditions.
- ENPP3 exhibits a distinct tissue expression profile and accounts for all cGAMP hydrolysis in ENPP1-deficient mice.
- Selective inhibition of ENPP3's cGAMP hydrolysis activity reduced cancer growth and metastasis in a STING-dependent manner.
- Both ENPP1 and ENPP3 are extracellular enzymes, highlighting the role of extracellular cGAMP in cell-cell immune communication.
Conclusions:
- ENPP1 and ENPP3 non-redundantly regulate extracellular cGAMP levels, dampening STING-mediated innate immune signaling.
- ENPP3 represents a novel therapeutic target for cancer immunotherapy by modulating extracellular cGAMP signaling.
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