Cell
Volume 185, Issue 13, 23 June 2022, Pages 2370-2386.e18
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Article
TIR domains of plant immune receptors are 2′,3′-cAMP/cGMP synthetases mediating cell death

https://doi.org/10.1016/j.cell.2022.04.032Get rights and content
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Highlights

  • Plant TIR proteins act as 2′,3′-cAMP/cGMP synthetases by hydrolyzing dsRNA/dsDNA

  • Cryo-EM structure reveals the mechanism of plant TIRs as bifunctional enzymes

  • 2′,3′-cAMP/cGMP are required for TIR-mediated cell death in plants

  • 2′,3′-cAMP/cGMP PDE negatively regulate TIR-mediated cell death in plants

Summary

2′,3′-cAMP is a positional isomer of the well-established second messenger 3′,5′-cAMP, but little is known about the biology of this noncanonical cyclic nucleotide monophosphate (cNMP). Toll/interleukin-1 receptor (TIR) domains of nucleotide-binding leucine-rich repeat (NLR) immune receptors have the NADase function necessary but insufficient to activate plant immune responses. Here, we show that plant TIR proteins, besides being NADases, act as 2′,3′-cAMP/cGMP synthetases by hydrolyzing RNA/DNA. Structural data show that a TIR domain adopts distinct oligomers with mutually exclusive NADase and synthetase activity. Mutations specifically disrupting the synthetase activity abrogate TIR-mediated cell death in Nicotiana benthamiana (Nb), supporting an important role for these cNMPs in TIR signaling. Furthermore, the Arabidopsis negative regulator of TIR-NLR signaling, NUDT7, displays 2′,3′-cAMP/cGMP but not 3′,5′-cAMP/cGMP phosphodiesterase activity and suppresses cell death activity of TIRs in Nb. Our study identifies a family of 2′,3′-cAMP/cGMP synthetases and establishes a critical role for them in plant immune responses.

Keywords

plant immunity
NLRs
TIRs
2′,3′-cAMP/cGMP synthetases
bifunctional enzymes
2′,3′-cAMP/cGMP phosphodiesterases

Data and code availability

The structures of the L7TIR-dsDNA initial state complex, intermediate state complex and end state complex were deposited in the Protein Data Bank (PDB) with PDB code: 7X5K, 7X5L, 7X5M, respectively. In the end state complex, a 2’,3’-cAMP bound L7TIR protomer was deposited in PDB with PDB code: 7VU8. This paper does not report original code. Any additional information required to reanalyze the data reported in this work paper is available from the lead contact upon request.

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These authors contributed equally

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Lead contact