Identification of extracellular membrane protein ENPP3 as a major cGAMP hydrolase, cementing cGAMP's role as an immunotransmitter.
bioRxiv
; 2024 Jan 13.
Article
en En
| MEDLINE
| ID: mdl-38260585
ABSTRACT
cGAMP is a second messenger that is synthesized in the cytosol upon detection of cytosolic dsDNA and passed between cells to facilitate downstream immune signaling. ENPP1, an extracellular enzyme, was the only metazoan cGAMP hydrolase known to regulate cGAMP levels to dampen anti-cancer immunity. Here, we uncover ENPP3 as the second and only other metazoan cGAMP hydrolase under homeostatic conditions. ENPP3 has a tissue expression pattern distinct from that of ENPP1 and accounts for all remaining cGAMP hydrolysis activity in mice lacking ENPP1. Importantly, we also show that as with ENPP1, selectively abolishing ENPP3's cGAMP hydrolase activity results in diminished cancer growth and metastasis of certain tumor types. 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 clearly shows that ENPP1 and ENPP3 non-redundantly dampen extracellular cGAMP-STING signaling, pointing to ENPP3 as a new target for cancer immunotherapy.
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1
Bases de datos:
MEDLINE
Tipo de estudio:
Diagnostic_studies
Idioma:
En
Revista:
BioRxiv
Año:
2024
Tipo del documento:
Article