Format

Send to

Choose Destination
Cell. 2019 Mar 7;176(6):1432-1446.e11. doi: 10.1016/j.cell.2019.01.049. Epub 2019 Feb 28.

Phosphoinositide Interactions Position cGAS at the Plasma Membrane to Ensure Efficient Distinction between Self- and Viral DNA.

Author information

1
Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
2
Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Departamento de Microbiología y Parasitología, Facultad de Farmacia. Universidad Complutense de Madrid e Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Plaza de Ramón y Cajal sn, 28040 Madrid, Spain.
3
Department of Microbiology, Harvard Medical School, Boston, MA, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
4
Department of Microbiology, Harvard Medical School, Boston, MA, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA, USA.
5
Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: jonathan.kagan@childrens.harvard.edu.

Abstract

The presence of DNA in the cytosol of mammalian cells is an unusual event that is often associated with genotoxic stress or viral infection. The enzyme cGAS is a sensor of cytosolic DNA that induces interferon and inflammatory responses that can be protective or pathologic, depending on the context. Along with other cytosolic innate immune receptors, cGAS is thought to diffuse throughout the cytosol in search of its DNA ligand. Herein, we report that cGAS is not a cytosolic protein but rather localizes to the plasma membrane via the actions of an N-terminal phosphoinositide-binding domain. This domain interacts selectively with PI(4,5)P2, and cGAS mutants defective for lipid binding are mislocalized to the cytosolic and nuclear compartments. Mislocalized cGAS induces potent interferon responses to genotoxic stress, but weaker responses to viral infection. These data establish the subcellular positioning of a cytosolic innate immune receptor as a mechanism that governs self-nonself discrimination.

KEYWORDS:

STING; cGAS; innate immunity; interferon; localization; macrophages; phosphoinositides

PMID:
30827685
PMCID:
PMC6697112
[Available on 2020-03-07]
DOI:
10.1016/j.cell.2019.01.049

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center