Work

Structure of Human cGAS Reveals a Conserved Family of Second-Messenger Enzymes in Innate Immunity

Year: 2013

Type: article

Abstract: Innate immune recognition of foreign nucleic acids induces protective interferon responses. Detection of cytosolic DNA triggers downstream immune signaling through activation of cyclic GMP-AMP synthase (cGAS). We report here the crystal structure of human cGAS, revealing an unanticipated zinc-ribbon DNA-binding domain appended to a core enzymatic nucleotidyltransferase scaffold. The catalytic core of cGAS is structurally homologous to the RNA-sensing enzyme, 2'-5' oligo-adenylate synthase (OAS), and divergent C-terminal domains account for specific ligand-activation requirements of each enzyme. We show that the cGAS zinc ribbon is essential for STING-dependent induction of the interferon response and that conserved amino acids displayed within the intervening loops are required for efficient cytosolic DNA recognition. These results demonstrate that cGAS and OAS define a family of innate immunity sensors and that structural divergence from a core nucleotidyltransferase enables second-messenger responses to distinct foreign nucleic acids.

Source: Cell Reports

DOI: 10.1016/j.celrep.2013.05.008

Authors: Philip J. Kranzusch, Amy Si-Ying Lee, James M. Berger, Jennifer A. Doudna

Institutions: Howard Hughes Medical Institute, University of California, Berkeley, Lawrence Berkeley National Laboratory

Language: English

Topic: interferon and immune responses

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $5,620

Funders: Howard Hughes Medical Institute, National Institute of General Medical Sciences