Toll/interleukin-1 receptor (TIR) domain-containing proteins have NAD-RNA decapping activity

Xufeng Wang, Dongli Yu, Jiancheng Yu, Hao Hu, Runlai Hang, Zachary Amador, Qi Chen, Jijie Chai and Xuemei Chen ()
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Xufeng Wang: Peking University
Dongli Yu: University of Cologne
Jiancheng Yu: University of Utah School of Medicine
Hao Hu: Peking University
Runlai Hang: Peking University
Zachary Amador: University of California
Qi Chen: University of Utah School of Medicine
Jijie Chai: University of Cologne
Xuemei Chen: Peking University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract The occurrence of NAD+ as a non-canonical RNA cap has been demonstrated in diverse organisms. TIR domain-containing proteins present in all kingdoms of life act in defense responses and can have NADase activity that hydrolyzes NAD+. Here, we show that TIR domain-containing proteins from several bacterial and one archaeal species can remove the NAM moiety from NAD-capped RNAs (NAD-RNAs). We demonstrate that the deNAMing activity of AbTir (from Acinetobacter baumannii) on NAD-RNA specifically produces a cyclic ADPR-RNA, which can be further decapped in vitro by known decapping enzymes. Heterologous expression of the wild-type but not a catalytic mutant AbTir in E. coli suppressed cell propagation and reduced the levels of NAD-RNAs from a subset of genes before cellular NAD+ levels are impacted. Collectively, the in vitro and in vivo analyses demonstrate that TIR domain-containing proteins can function as a deNAMing enzyme of NAD-RNAs, raising the possibility of TIR domain proteins acting in gene expression regulation.

Date: 2024
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DOI: 10.1038/s41467-024-46499-y

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