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12.08.2022

A base-line cellular antiviral state is maintained by cGAS and its most frequent naturally occurring variant rs610913

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Pattern recognition receptors (PRRs) of the innate immune system serve as a first line defence against invading pathogens. The cyclic-GMP-AMP-synthase (cGAS) activates a STING/IRF3-driven antiviral response upon binding to dsDNA that efficiently restricts pathogen replication and spread. Recently, a group of interdisciplinary researchers headed by Prof. Dr. Christine Goffinet from the Institute of Virology at Charité – Universitätsmedizin Berlin assessed the structural and functional properties of rs610913, the most frequently occurring SNP in the cGAS-encoding gene. rs610913, encoding for a single amino acid exchange from proline to histidine at position 261, is potentially of high public health relevance due to its global allele frequency of >0.5. Data from the International Collaboration for the Genomics of HIV suggested that rs610913 nominally associates with HIV-1 acquisition in vivo. Further, molecular modelling of cGAS (P261H) suggested the presence of an additional binding site for a potential cellular co-factor in cGAS dimers. Using cGAS-deficient cell culture models, cells reconstituted with cGAS(P261) expression displayed a tendency towards lower innate immune activation following DNA-sensing as compared to cGAS(WT)-expressing cells, which however was not translated into an altered restriction of viral infections, suggesting a largely intact DNA-sensing ability. Interestingly, cGAS(WT) and cGAS(P261)-expressing cells, in contrast to cGAS-deficient cells and cells expressing a catalytically inactive cGAS mutant,  shared a steady-state innate immune activation even in the absence of infection, which decreased cellular susceptibility to incoming viruses. Consequently, cGAS-mediated restriction was not limited to viruses harbouring DNA genomes (HSV-1) or DNA-containing replication intermediates (HIV-1) but was also detected for RNA viruses (Chikungunya virus). This study underlines that cGAS’ antiviral activity exceeds the direct sensing of incoming viral DNA genomes, but maintains uninfected cells in a broad, base-line antiviral state through expression of antiviral factors. This study underscores the important role of cGAS beyond sensing newly produced viral DNA.

A base-line cellular antiviral state is maintained by cGAS and its most frequent naturally occurring variant rs610913

Kazmierski, J., Elsner, C., Döhner, K., Shuting, X., Ducroux, A., Pott, F., Jansen, J., Thorball, C.W., Zeymer, O., Zhou, X., Fedorov, R., Fellay, J., Löffler, M.W., Weber, A.N.R., Sodeik, B., and Goffinet, C.

Journal of Immunology, 2022.

This study was co-financed by the German Research Foundation and by BIH.

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