Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity
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Description
Resisting and tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here genomic analyses of anatomically modern humans, extinct Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded substitutions at non-catalytic residues of the ubiquitin protease OTU domain that diminished IκB kinase-dependent phosphorylation and activation of A20. Two TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits seemed to be beneficial by increasing immunity without causing spontaneous inflammatory disease: A20 T108A;I207L, originating in Denisovans and introgressed in modern humans throughout Oceania, and A20 I325N, from an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y, caused spontaneous inflammatory disease in humans and mice. Analysis of the partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for enhanced immunity.
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| ID Code: | 203470 | ||
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| Item Type: | Contribution to Journal (Journal Article) | ||
| Refereed: | Yes | ||
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| Measurements or Duration: | 12 pages | ||
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| ISSN: | 1529-2908 | ||
| Pure ID: | 67112499 | ||
| Funding Information: | This manuscript is dedicated to the memory of Susan Watson, who led the isolation of the I325N mouse. We thank the National Computational Infrastructure, Xenon systems, Nvidia and the Multi-modal Australian ScienceS Imaging and Visualization Environment (MASSIVE; http://www.massive.org.au/) for computing resources. We thank O. Venn, I. Mathieson, B. Llamas, Y. Souilmi, R. Tobler and A. Cooper for stimulating discussions. C.N.J. thanks J. Cyster for mentorship. We thank K. Newton and V. Dixit for reagents (Genentech). We thank M. Flodström-Tullberg (Karolinska Institutet) for kindly providing coxsackievirus B4 strain E2. This study makes use of data generated by the Telethon Kids Institute. A full list of the investigators who contributed to the generation of the data is available from http://bioinformatics.childhealthresearch.org.au/AGHS. We thank CIRCA for collecting and coordinating human samples (http://www.garvan. org.au/research/collaborative-programs/circa/about-circa). Funding for the project was provided by the National Health and Medical Research Council of Australia (NHMRC) under award 634301. N.W.Z. was supported by an Australian postgraduate award and is supported by the International Pancreas and Islet Transplant Association Derek Gray Scholarship. A.M.B. was an NHMRC Senior Research Fellow (1022688). S.G.T. was a Principal Research Fellow (1042925) of the NHMRC. C.C.G. was supported by the Bill and Patricia Ritchie Chair and by an NHMRC Senior Principal Research Fellowship. S.T.G. was supported by an NHMRC Senior Research Fellowship. The research was supported by grants to C.C.G. from the NIH (AI52127, AI054523, AI100627) and NHMRC (1016953, 585490, 1081858) and to S.T.G. from the NIH (DK076169) and NHMRC (1130222, 1140691). CIRCA was supported by the Jeffrey Modell Foundation, the John Cook Brown Foundation and the Sydney Children’s Hospital Network. | ||
| Copyright Owner: | Springer Nature Limited | ||
| Copyright Statement: | This work is covered by copyright. Unless the document is being made available under a Creative Commons Licence, you must assume that re-use is limited to personal use and that permission from the copyright owner must be obtained for all other uses. If the document is available under a Creative Commons License (or other specified license) then refer to the Licence for details of permitted re-use. It is a condition of access that users recognise and abide by the legal requirements associated with these rights. If you believe that this work infringes copyright please provide details by email to qut.copyright@qut.edu.au | ||
| Deposited On: | 26 Aug 2020 05:28 | ||
| Last Modified: | 26 Jul 2024 15:09 |
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