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

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.

MicroRNAs for Virus Pathogenicity and Host Responses, Identified in SARS-CoV-2 Genomes, May Play Roles in Viral-Host Co-Evolution in Putative Zoonotic Host Species

“…These findings indicate that cow may be a putative intermediate host between pangolin and human, but this will require further investigation. While pangolins have been found to have unusual resistance against viral, including coronavirus, infection [ 41 , 42 ], the cow is also well known for its unusual antiviral responses, including those via neutralizing antibodies (“cattlebodies”), which are effective, for example, against retroviral infections such as HIV [ 43 ], and are also under investigation for their effectiveness against SARS-CoV-2. Coronaviruses are well known in cattle and can cause gastroenteritis, respiratory disease, winter dysentery and shipping fever pneumonia [ 44 ].…”

Role of Post-Translational Modifications of cGAS in Innate Immunity

“…It is notable that cGAS knockout mice are healthy and normally developed in a barrier facility [ 60 ]. Furthermore, cytosolic DNA sensing through cGAS and STING is inactivated due to gene mutations in wild pangolins [ 61 ]. Thus, future works will be needed to use genetic tools to establish mouse cancer models in cGAS deficiency or PTM deficiency backgrounds.…”

Combined proteomics and transcriptomics reveal the genetic basis underlying the differentiation of skin appendages and immunity in pangolin

“…Previous studies have found that some key genes related to immune function in the innate immune system of pangolins are pseudogenized or mutated, resulting in the loss of their immune pathways and functions involved in resistance to viral or bacterial invasion, and it is speculated that pangolins may have some undiscovered immune replacement compensation mechanisms 27 , 28 . However, we do not agree with some scholars who suggest that the evolution of pangolin scales is an innovative compensation for low immune function of the back skin 7 .…”