小柯机器人

澳大利亚加文医学研究所的Daniel Christ和Christopher C. Goodnow等研究人员合作发现，丹尼索瓦人、现代人类和小鼠中的TNFAIP3等位基因通过改变A20蛋白的磷酸化位点来调节免疫力。这一研究成果2019年9月18日在线发表于《自然—免疫学》。

在解剖学上现代人类、已灭绝的丹尼索万人和小鼠的基因组分析揭示了TNFAIP3系列等位基因，并在编码的免疫应答抑制蛋白A20上存在变化。每个TNFAIP3等位基因在泛素蛋白酶OTU结构域的非催化残基处编码改变，从而减少IκB激酶依赖性磷酸化和A20的活化。编码具有部分磷酸化缺陷的A20蛋白的两个TNFAIP3等位基因似乎是有好处的，其通过增加免疫力而不引起自发性炎性疾病，这些突变包括：A20 T108A;I207L，起源于丹尼索万人并在整个大洋洲的现代人中渗入，而A20 I325N，来自N-乙基-N-亚硝基脲（ENU）诱变小鼠品系。相比之下，编码具有95％磷酸化损失的A20蛋白的罕见人TNFAIP3等位基因C243Y在人和小鼠中引起自发性炎性疾病。对小鼠中A20 I325N等位基因（蛋白能够部分被磷酸化）的分析显示出对细菌脂多糖和痘病毒接种耐受性的降低作为增强免疫力的权衡。

据了解，抵抗和耐受微生物是感染存活的替代策略，但对控制这种平衡的进化机制知之甚少。

附：英文原文

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

Author: 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 Chaudhri, Gunasegaran 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

Issue&Volume: 2019-09-18

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.

DOI: 10.1038/s41590-019-0492-0

Source: https://www.nature.com/articles/s41590-019-0492-0

Nature Immunology：《自然—免疫学》，创刊于2000年。隶属于施普林格·自然出版集团，最新IF：31.25
官方网址：https://www.nature.com/ni/
投稿链接：https://mts-ni.nature.com/cgi-bin/main.plex