ArticleNature immunology2019
Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity.
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Article in Nature immunology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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41citing papers in PubMed
3.6field-weighted citation impact, top 6% of its field
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Who cites it
41 citing papers in PubMed, 71 citations in OpenAlex.
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- A20 in Kidney Transplantation and Autoimmunity.International journal of molecular sciences · 2024Review
- The Complexity of Being A20: From Biological Functions to Genetic Associations.Journal of clinical immunology · 2024Review
- More than a decade of genetic research on the Denisovans.Nature reviews. Genetics · 2024Review
- Protein citrullination and NET formation do not contribute to the pathology of A20/TNFAIP3 mutant mice.Scientific reports · 2023Article
- A Model of iPSC-Derived Macrophages withInternational journal of molecular sciences · 2023Article
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Authors and funding
56 authors at 12 institutions in 4 countries.
Nathan W Zammit *Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.ORCID http://orcid.org/0000-0002-3694-2951
Owen M Siggs *Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.ORCID http://orcid.org/0000-0003-2840-4851
Paul E GrayDepartment of Immunology and Infectious Diseases, Sydney Children's Hospital, Randwick, New South Wales, Australia.
Keisuke HorikawaJohn Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
David B LangleyGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Stacey N WaltersGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Stephen R DaleyJohn Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.ORCID http://orcid.org/0000-0002-5870-644X
Claudia LoetschGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Joanna WarrenGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Jin Yan YapGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Daniele CultroneGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Amanda RussellGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.ORCID http://orcid.org/0000-0001-7148-1081
Elisabeth K MalleGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Jeanette E VillanuevaGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Mark J CowleyGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Velimir GayevskiyGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Marcel E DingerGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.ORCID http://orcid.org/0000-0003-4423-934X
Robert BrinkGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
David ZahraGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.ORCID http://orcid.org/0000-0002-4433-2766
Geeta ChaudhriJohn Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
Gunasegaran KarupiahJohn Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
Belinda WhittleJohn Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
Carla RootsJohn Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
Edward BertramJohn Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
Michiko YamadaJohn Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
Yogesh JeelallJohn Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
Anselm EndersJohn Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.ORCID http://orcid.org/0000-0001-5933-6463
Benjamin E CliftonResearch School of Chemistry, The Australian National University, Canberra, Australian Capital Territory, Australia.
Peter D MabbittResearch School of Chemistry, The Australian National University, Canberra, Australian Capital Territory, Australia.
Colin J JacksonResearch School of Chemistry, The Australian National University, Canberra, Australian Capital Territory, Australia.ORCID http://orcid.org/0000-0001-6150-3822
Susan R WatsonDepartment of Microbiology & Immunology and the Parker Institute for Cancer Immunotherapy, University of California San Francisco, San Francisco, CA, USA.
Craig N JenneDepartment of Microbiology & Immunology and the Parker Institute for Cancer Immunotherapy, University of California San Francisco, San Francisco, CA, USA.ORCID http://orcid.org/0000-0001-8637-0181
Lewis L LanierDepartment of Microbiology & Immunology and the Parker Institute for Cancer Immunotherapy, University of California San Francisco, San Francisco, CA, USA.ORCID http://orcid.org/0000-0003-1308-3952
Tim WiltshireEshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
Matthew H SpitzerDepartment of Microbiology & Immunology, Stanford University, Stanford, CA, USA.ORCID http://orcid.org/0000-0002-5291-3819
Garry P NolanDepartment of Microbiology & Immunology, Stanford University, Stanford, CA, USA.
Frank SchmitzSeattle Biomedical Research Institute, Seattle, WA, USA.
Alan AderemSeattle Biomedical Research Institute, Seattle, WA, USA.
Benjamin T PorebskiDepartment of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.ORCID http://orcid.org/0000-0003-1398-0442
Ashley M BuckleDepartment of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.ORCID http://orcid.org/0000-0003-2943-9044
Derek W AbbottDepartment of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
John B ZieglerDepartment of Immunology and Infectious Diseases, Sydney Children's Hospital, Randwick, New South Wales, Australia.
Maria E CraigSchool of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia.
Paul Benitez-AguirreDepartment of Haematology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
Juliana TeoDepartment of Haematology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
Stuart G TangyeGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.ORCID http://orcid.org/0000-0002-5360-5180
Cecile KingGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Melanie WongDepartment of Haematology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
Murray P CoxSchool of Fundamental Sciences, Massey University, Palmerston North, New Zealand.ORCID http://orcid.org/0000-0003-1936-0236
Wilson PhungGenentech Inc., South San Francisco, CA, USA.ORCID http://orcid.org/0000-0001-7793-3931
Jia TangGenentech Inc., South San Francisco, CA, USA.
Wendy SandovalGenentech Inc., South San Francisco, CA, USA.
Ingrid E WertzGenentech Inc., South San Francisco, CA, USA.
Daniel ChristGarvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.ORCID http://orcid.org/0000-0002-7313-3977
Christopher C Goodnow *Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. c.goodnow@garvan.org.au.ORCID http://orcid.org/0000-0001-5296-6155
Shane T Grey *Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. s.grey@garvan.org.au.ORCID http://orcid.org/0000-0003-2160-1625
Garvan Institute of Medical Research · AUAustralian National University · AUChildren's Hospital at Westmead · AUUniversity of California, San Francisco · USCenter for Infectious Disease Research · USMonash University · AUUNSW Sydney · AUMassey University · NZStanford University · USUniversity of Calgary · CAUniversity of North Carolina at Chapel Hill · USUniversity School · US
Funding
Systems Approach to Innate Immunity-Inflammation-SepsisU54AI054523 · NIAID · SCRIPPS RESEARCH INSTITUTE, THE · PI ULEVITCH, RICHARD J · 2002 to 2006
$28.0MGenes for Tolerance and Immunity ConsortiumR01AI052127 · NIAID · AUSTRALIAN NATIONAL UNIVERSITY · PI GOODNOW, CHRISTOPHER CARL · 2002 to 2006
$6.3MNIAID NIH HHS R01 AI052127NIAID NIH HHS U54 AI054523
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.
Indexed as
AllelesAnimalsExtinction, BiologicalHumansImmunityInflammationMiceMice, Inbred C57BLMice, TransgenicMutation, MissensePhosphorylationPoxviridaePoxviridae InfectionsProtein DomainsTumor Necrosis Factor alpha-Induced Protein 3Tumor Necrosis Factor alpha-Induced Protein 3
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