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

Nathan W Zammit, Owen M Siggs, Paul E Gray, Keisuke Horikawa, David B Langley, Stacey N Walters, Stephen R Daley, Claudia Loetsch, Joanna Warren, Jin Yan Yap, Daniele Cultrone, Amanda Russell, Elisabeth K Malle, Jeanette E Villanueva, Mark J Cowley, Velimir Gayevskiy, Marcel E Dinger, Robert Brink, David Zahra, Geeta ChaudhriGunasegaran Karupiah, Belinda Whittle, Carla Roots, Edward Bertram, Michiko Yamada, Yogesh Jeelall, Anselm Enders, Benjamin E Clifton, Peter D Mabbitt, Colin J Jackson, Susan R Watson, Craig N Jenne, Lewis L Lanier, Tim Wiltshire, Matthew H Spitzer, Garry P Nolan, Frank Schmitz, Alan Aderem, Benjamin T Porebski, Ashley M Buckle, Derek W Abbott, John B Ziegler, Maria E Craig, Paul Benitez-Aguirre, Juliana Teo, Stuart G Tangye, Cecile King, Melanie Wong, Murray P Cox, Wilson Phung, Jia Tang, Wendy Sandoval, Ingrid E Wertz, Daniel Christ, Christopher C Goodnow, Shane T Grey

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1299-1310
Number of pages12
JournalNature Immunology
Volume20
Issue number10
DOIs
Publication statusPublished - 18 Sep 2019

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Immunity
Alleles
Phosphorylation
Oceania
Ethylnitrosourea
Poxviridae
Hominidae
Ubiquitin
Lipopolysaccharides
Proteins
Peptide Hydrolases
Phosphotransferases
Infection

Cite this

Zammit, N. W., Siggs, O. M., Gray, P. E., Horikawa, K., Langley, D. B., Walters, S. N., ... Grey, S. T. (2019). Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity. Nature Immunology, 20(10), 1299-1310. https://doi.org/10.1038/s41590-019-0492-0
Zammit, Nathan W ; Siggs, Owen M ; Gray, Paul E ; Horikawa, Keisuke ; Langley, David B ; Walters, Stacey N ; Daley, Stephen R ; Loetsch, Claudia ; Warren, Joanna ; Yap, Jin Yan ; Cultrone, Daniele ; Russell, Amanda ; Malle, Elisabeth K ; Villanueva, Jeanette E ; Cowley, Mark J ; Gayevskiy, Velimir ; Dinger, Marcel E ; Brink, Robert ; Zahra, David ; Chaudhri, Geeta ; Karupiah, Gunasegaran ; Whittle, Belinda ; Roots, Carla ; Bertram, Edward ; Yamada, Michiko ; Jeelall, Yogesh ; Enders, Anselm ; Clifton, Benjamin E ; Mabbitt, Peter D ; Jackson, Colin J ; Watson, Susan R ; Jenne, Craig N ; Lanier, Lewis L ; Wiltshire, Tim ; Spitzer, Matthew H ; Nolan, Garry P ; Schmitz, Frank ; Aderem, Alan ; Porebski, Benjamin T ; Buckle, Ashley M ; Abbott, Derek W ; Ziegler, John B ; Craig, Maria E ; Benitez-Aguirre, Paul ; Teo, Juliana ; Tangye, Stuart G ; King, Cecile ; Wong, Melanie ; Cox, Murray P ; Phung, Wilson ; Tang, Jia ; Sandoval, Wendy ; Wertz, Ingrid E ; Christ, Daniel ; Goodnow, Christopher C ; Grey, Shane T. / Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity. In: Nature Immunology. 2019 ; Vol. 20, No. 10. pp. 1299-1310.
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abstract = "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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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, 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 & Grey, ST 2019, 'Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity', Nature Immunology, vol. 20, no. 10, pp. 1299-1310. https://doi.org/10.1038/s41590-019-0492-0

Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity. / Zammit, Nathan W; Siggs, Owen M; Gray, Paul E; Horikawa, Keisuke; Langley, David B; Walters, Stacey N; Daley, Stephen R; Loetsch, Claudia; Warren, Joanna; Yap, Jin Yan; Cultrone, Daniele; Russell, Amanda; Malle, Elisabeth K; Villanueva, Jeanette E; Cowley, Mark J; Gayevskiy, Velimir; Dinger, Marcel E; Brink, Robert; Zahra, David; Chaudhri, Geeta; Karupiah, Gunasegaran; Whittle, Belinda; Roots, Carla; Bertram, Edward; Yamada, Michiko; Jeelall, Yogesh; Enders, Anselm; Clifton, Benjamin E; Mabbitt, Peter D; Jackson, Colin J; Watson, Susan R; Jenne, Craig N; Lanier, Lewis L; Wiltshire, Tim; Spitzer, Matthew H; Nolan, Garry P; Schmitz, Frank; Aderem, Alan; Porebski, Benjamin T; Buckle, Ashley M; Abbott, Derek W; Ziegler, John B; Craig, Maria E; Benitez-Aguirre, Paul; Teo, Juliana; Tangye, Stuart G; King, Cecile; Wong, Melanie; Cox, Murray P; Phung, Wilson; Tang, Jia; Sandoval, Wendy; Wertz, Ingrid E; Christ, Daniel; Goodnow, Christopher C; Grey, Shane T.

In: Nature Immunology, Vol. 20, No. 10, 18.09.2019, p. 1299-1310.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity

AU - Zammit, Nathan W

AU - Siggs, Owen M

AU - Gray, Paul E

AU - Horikawa, Keisuke

AU - Langley, David B

AU - Walters, Stacey N

AU - Daley, Stephen R

AU - Loetsch, Claudia

AU - Warren, Joanna

AU - Yap, Jin Yan

AU - Cultrone, Daniele

AU - Russell, Amanda

AU - Malle, Elisabeth K

AU - Villanueva, Jeanette E

AU - Cowley, Mark J

AU - Gayevskiy, Velimir

AU - Dinger, Marcel E

AU - Brink, Robert

AU - Zahra, David

AU - Chaudhri, Geeta

AU - Karupiah, Gunasegaran

AU - Whittle, Belinda

AU - Roots, Carla

AU - Bertram, Edward

AU - Yamada, Michiko

AU - Jeelall, Yogesh

AU - Enders, Anselm

AU - Clifton, Benjamin E

AU - Mabbitt, Peter D

AU - Jackson, Colin J

AU - Watson, Susan R

AU - Jenne, Craig N

AU - Lanier, Lewis L

AU - Wiltshire, Tim

AU - Spitzer, Matthew H

AU - Nolan, Garry P

AU - Schmitz, Frank

AU - Aderem, Alan

AU - Porebski, Benjamin T

AU - Buckle, Ashley M

AU - Abbott, Derek W

AU - Ziegler, John B

AU - Craig, Maria E

AU - Benitez-Aguirre, Paul

AU - Teo, Juliana

AU - Tangye, Stuart G

AU - King, Cecile

AU - Wong, Melanie

AU - Cox, Murray P

AU - Phung, Wilson

AU - Tang, Jia

AU - Sandoval, Wendy

AU - Wertz, Ingrid E

AU - Christ, Daniel

AU - Goodnow, Christopher C

AU - Grey, Shane T

PY - 2019/9/18

Y1 - 2019/9/18

N2 - 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.

AB - 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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DO - 10.1038/s41590-019-0492-0

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JO - Nature Immunology

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Zammit NW, Siggs OM, Gray PE, Horikawa K, Langley DB, Walters SN et al. Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity. Nature Immunology. 2019 Sep 18;20(10):1299-1310. https://doi.org/10.1038/s41590-019-0492-0