Structure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance

Wen Zhou; Aaron T. Whiteley; Carina C. de Oliveira Mann; Benjamin R. Morehouse; Radosław P. Nowak; Eric S. Fischer; Nathanael S. Gray; John J. Mekalanos; Philip J. Kranzusch

doi:10.1016/j.cell.2018.06.026

Structure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance

Wen Zhou, Aaron T. Whiteley, Carina C. de Oliveira Mann, Benjamin R. Morehouse, Radosław P. Nowak, Eric S. Fischer, Nathanael S. Gray, John J. Mekalanos, Philip J. Kranzusch

Research output: Contribution to journal › Article › peer-review

258 Scopus citations

Abstract

Cyclic GMP–AMP synthase (cGAS) recognition of cytosolic DNA is critical for immune responses to pathogen replication, cellular stress, and cancer. Existing structures of the mouse cGAS–DNA complex provide a model for enzyme activation but do not explain why human cGAS exhibits severely reduced levels of cyclic GMP–AMP (cGAMP) synthesis compared to other mammals. Here, we discover that enhanced DNA-length specificity restrains human cGAS activation. Using reconstitution of cGAMP signaling in bacteria, we mapped the determinant of human cGAS regulation to two amino acid substitutions in the DNA-binding surface. Human-specific substitutions are necessary and sufficient to direct preferential detection of long DNA. Crystal structures reveal why removal of human substitutions relaxes DNA-length specificity and explain how human-specific DNA interactions favor cGAS oligomerization. These results define how DNA-sensing in humans adapted for enhanced specificity and provide a model of the active human cGAS–DNA complex to enable structure-guided design of cGAS therapeutics.

Original language	English
Pages (from-to)	300-311.e11
Journal	Cell
Volume	174
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2018.06.026
State	Published - 12 Jul 2018
Externally published	Yes

Keywords

STING
cGAS
innate immunity
structural biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2018.06.026

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title = "Structure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance",

abstract = "Cyclic GMP–AMP synthase (cGAS) recognition of cytosolic DNA is critical for immune responses to pathogen replication, cellular stress, and cancer. Existing structures of the mouse cGAS–DNA complex provide a model for enzyme activation but do not explain why human cGAS exhibits severely reduced levels of cyclic GMP–AMP (cGAMP) synthesis compared to other mammals. Here, we discover that enhanced DNA-length specificity restrains human cGAS activation. Using reconstitution of cGAMP signaling in bacteria, we mapped the determinant of human cGAS regulation to two amino acid substitutions in the DNA-binding surface. Human-specific substitutions are necessary and sufficient to direct preferential detection of long DNA. Crystal structures reveal why removal of human substitutions relaxes DNA-length specificity and explain how human-specific DNA interactions favor cGAS oligomerization. These results define how DNA-sensing in humans adapted for enhanced specificity and provide a model of the active human cGAS–DNA complex to enable structure-guided design of cGAS therapeutics.",

keywords = "STING, cGAS, innate immunity, structural biology",

author = "Wen Zhou and Whiteley, {Aaron T.} and {de Oliveira Mann}, {Carina C.} and Morehouse, {Benjamin R.} and Nowak, {Rados{\l}aw P.} and Fischer, {Eric S.} and Gray, {Nathanael S.} and Mekalanos, {John J.} and Kranzusch, {Philip J.}",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

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doi = "10.1016/j.cell.2018.06.026",

language = "English",

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AU - Zhou, Wen

AU - Whiteley, Aaron T.

AU - de Oliveira Mann, Carina C.

AU - Morehouse, Benjamin R.

AU - Nowak, Radosław P.

AU - Fischer, Eric S.

AU - Gray, Nathanael S.

AU - Mekalanos, John J.

AU - Kranzusch, Philip J.

PY - 2018/7/12

Y1 - 2018/7/12

N2 - Cyclic GMP–AMP synthase (cGAS) recognition of cytosolic DNA is critical for immune responses to pathogen replication, cellular stress, and cancer. Existing structures of the mouse cGAS–DNA complex provide a model for enzyme activation but do not explain why human cGAS exhibits severely reduced levels of cyclic GMP–AMP (cGAMP) synthesis compared to other mammals. Here, we discover that enhanced DNA-length specificity restrains human cGAS activation. Using reconstitution of cGAMP signaling in bacteria, we mapped the determinant of human cGAS regulation to two amino acid substitutions in the DNA-binding surface. Human-specific substitutions are necessary and sufficient to direct preferential detection of long DNA. Crystal structures reveal why removal of human substitutions relaxes DNA-length specificity and explain how human-specific DNA interactions favor cGAS oligomerization. These results define how DNA-sensing in humans adapted for enhanced specificity and provide a model of the active human cGAS–DNA complex to enable structure-guided design of cGAS therapeutics.

AB - Cyclic GMP–AMP synthase (cGAS) recognition of cytosolic DNA is critical for immune responses to pathogen replication, cellular stress, and cancer. Existing structures of the mouse cGAS–DNA complex provide a model for enzyme activation but do not explain why human cGAS exhibits severely reduced levels of cyclic GMP–AMP (cGAMP) synthesis compared to other mammals. Here, we discover that enhanced DNA-length specificity restrains human cGAS activation. Using reconstitution of cGAMP signaling in bacteria, we mapped the determinant of human cGAS regulation to two amino acid substitutions in the DNA-binding surface. Human-specific substitutions are necessary and sufficient to direct preferential detection of long DNA. Crystal structures reveal why removal of human substitutions relaxes DNA-length specificity and explain how human-specific DNA interactions favor cGAS oligomerization. These results define how DNA-sensing in humans adapted for enhanced specificity and provide a model of the active human cGAS–DNA complex to enable structure-guided design of cGAS therapeutics.

KW - STING

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KW - innate immunity

KW - structural biology

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DO - 10.1016/j.cell.2018.06.026

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SN - 0092-8674

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JO - Cell

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IS - 2

ER -

Structure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance

Abstract

Keywords

UN SDGs

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