ENPP1’s regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating STING signaling

Carozza, Jacqueline A.; Cordova, Anthony F.; Brown, Jenifer A.; AlSaif, Yasmeen; Böhnert, Volker; Cao, Xujun; Mardjuki, Rachel E.; Skariah, Gemini; Fernandez, Daniel; Li, Lingyin

doi:10.1073/pnas.2119189119

ENPP1’s regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating STING signaling

Journal Article · Thu May 19 00:00:00 EDT 2022 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.2119189119· OSTI ID:2471727

Carozza, Jacqueline A. ^[1]; ^[1]; Brown, Jenifer A. ^[1]; ^[1]; Böhnert, Volker ^[1]; ^[1]; Mardjuki, Rachel E. ^[1]; Skariah, Gemini ^[1]; ^[1]; Li, Lingyin ^[1]

Stanford University, CA (United States)

The metazoan innate immune second messenger 2'3'-cGAMP is present both inside and outside cells. However, only extracellular cGAMP can be negatively regulated by the extracellular hydrolase ENPP1. Here, we determine whether ENPP1’s regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating stimulator of interferon genes (STING) signaling. We identified ENPP1^H362A, a point mutation that cannot degrade the 2'-5' linkage in cGAMP while maintaining otherwise normal function. The selectivity of this histidine is conserved down to bacterial nucleotide pyrophosphatase/phosphodiesterase (NPP), allowing structural analysis and suggesting an unexplored ancient history of 2'-5' cyclic dinucleotides. Enpp1^H362A mice demonstrated that extracellular cGAMP is not responsible for the devastating phenotype in ENPP1-null humans and mice but is responsible for antiviral immunity and systemic inflammation. Our data define extracellular cGAMP as a pivotal STING activator, identify an evolutionarily critical role for ENPP1 in regulating inflammation, and suggest a therapeutic strategy for viral and inflammatory conditions by manipulating ENPP1 activity.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2471727

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 21 Vol. 119; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
ENPP1
STING
Science & Technology - Other Topics
cGAMP
extracellular cGAMP
immunotransmitter

ENPP1’s regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating STING signaling

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