Cytosolic DNA sensing through cGAS and STING is inactivated by gene mutations in pangolins.

Apoptosis : an International Journal on Programmed Cell Death
Heinz FischerLeopold Eckhart

Abstract

The release of DNA into the cytoplasm upon damage to the nucleus or during viral infection triggers an interferon-mediated defense response, inflammation and cell death. In human cells cytoplasmic DNA is sensed by cyclic GMP-AMP Synthase (cGAS) and Absent In Melanoma 2 (AIM2). Here, we report the identification of a "natural knockout" model of cGAS. Comparative genomics of phylogenetically diverse mammalian species showed that cGAS and its interaction partner Stimulator of Interferon Genes (STING) have been inactivated by mutations in the Malayan pangolin whereas other mammals retained intact copies of these genes. The coding sequences of CGAS and STING1 are also disrupted by premature stop codons and frame-shift mutations in Chinese and tree pangolins, suggesting that expression of these genes was lost in a common ancestor of all pangolins that lived more than 20 million years ago. AIM2 is retained in a functional form in pangolins whereas it is inactivated by mutations in carnivorans, the phylogenetic sister group of pangolins. The deficiency of cGAS and STING points to the existence of alternative mechanisms of controlling cytoplasmic DNA-associated cell damage and viral infections in pangolins.

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Citations

Oct 28, 2020·International Journal of Molecular Sciences·Yakun Wu, Shitao Li
Feb 3, 2021·History and Philosophy of the Life Sciences·Ulrich E Stegmann
Dec 18, 2020·Frontiers in Immunology·Ayesha ZahidTengchuan Jin
Aug 21, 2021·Annual Review of Genetics·Yang ZhaoVera Gorbunova

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Methods Mentioned

BETA
whole genome

Software Mentioned

Basic Local Alignment Search Tool ( BLAST )

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