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Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity

Zammit, NW, Siggs, OM, Gray, PE, Horikawa, K, Langley, DB, Walters, SN, Daley, SR, Loetsch, C, Warren, J, Yap, JY, Cultrone, D, Russell, A, Malle, EK, Villanueva, JE, Cowley, MJ, Gayevskiy, V, Dinger, ME, Brink, R, Zahra, D, Chaudhri, G, Karupiah, G ORCID: 0000-0001-6306-4405, Whittle, B, Roots, C, Bertram, E, Yamada, M, Jeelall, Y, Enders, A, Clifton, BE, Mabbitt, PD, Jackson, CJ, Watson, SR, Jenne, CN, Lanier, LL, Wiltshire, T, Spitzer, MH, Nolan, GP, Schmitz, F, Aderem, A, Porebski, BT, Buckle, AM, Abbott, DW, Ziegler, JB, Craig, ME, Benitez-Aguirre, P, Teo, J, Tangye, SG, King, C, Wong, M, Cox, MP, Phung, W, Tang, J, Sandoval, W, Wertz, IE, Christ, D, Goodnow, CC and Grey, ST 2019 , 'Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity' , Nature Immunology, vol. 20, no. 10 , pp. 1299-1310 , doi: 10.1038/s41590-019-0492-0.

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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.

Item Type: Article
Authors/Creators:Zammit, NW and Siggs, OM and Gray, PE and Horikawa, K and Langley, DB and Walters, SN and Daley, SR and Loetsch, C and Warren, J and Yap, JY and Cultrone, D and Russell, A and Malle, EK and Villanueva, JE and Cowley, MJ and Gayevskiy, V and Dinger, ME and Brink, R and Zahra, D and Chaudhri, G and Karupiah, G and Whittle, B and Roots, C and Bertram, E and Yamada, M and Jeelall, Y and Enders, A and Clifton, BE and Mabbitt, PD and Jackson, CJ and Watson, SR and Jenne, CN and Lanier, LL and Wiltshire, T and Spitzer, MH and Nolan, GP and Schmitz, F and Aderem, A and Porebski, BT and Buckle, AM and Abbott, DW and Ziegler, JB and Craig, ME and Benitez-Aguirre, P and Teo, J and Tangye, SG and King, C and Wong, M and Cox, MP and Phung, W and Tang, J and Sandoval, W and Wertz, IE and Christ, D and Goodnow, CC and Grey, ST
Keywords: TNF Alpha Induced Protein 3, modern human, Denisovan, mouse, microbial immunity, immune tolerance, inflammation and immunopathology
Journal or Publication Title: Nature Immunology
Publisher: Nature Publishing Group
ISSN: 1529-2908
DOI / ID Number: 10.1038/s41590-019-0492-0
Copyright Information:

© The Author(s), under exclusive licence to Springer Nature America, Inc. 2019

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