School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia.
Science. 2022 Sep 30;377(6614):eadc8969. doi: 10.1126/science.adc8969.
Cyclic adenosine diphosphate (ADP)-ribose (cADPR) isomers are signaling molecules produced by bacterial and plant Toll/interleukin-1 receptor (TIR) domains via nicotinamide adenine dinucleotide (oxidized form) (NAD) hydrolysis. We show that v-cADPR (2'cADPR) and v2-cADPR (3'cADPR) isomers are cyclized by O-glycosidic bond formation between the ribose moieties in ADPR. Structures of 2'cADPR-producing TIR domains reveal conformational changes that lead to an active assembly that resembles those of Toll-like receptor adaptor TIR domains. Mutagenesis reveals a conserved tryptophan that is essential for cyclization. We show that 3'cADPR is an activator of ThsA effector proteins from the bacterial antiphage defense system termed Thoeris and a suppressor of plant immunity when produced by the effector HopAM1. Collectively, our results reveal the molecular basis of cADPR isomer production and establish 3'cADPR in bacteria as an antiviral and plant immunity-suppressing signaling molecule.
环腺苷二磷酸核糖（cADPR）异构体是细菌和植物 Toll/白细胞介素-1 受体（TIR）结构域通过烟酰胺腺嘌呤二核苷酸（氧化形式）（NAD）水解产生的信号分子。我们表明，v-cADPR（2'cADPR）和 v2-cADPR（3'cADPR）异构体通过 ADPR 中核糖部分之间的 O-糖苷键形成环化。产生 2'cADPR 的 TIR 结构域的结构揭示了导致类似于 Toll 样受体衔接子 TIR 结构域的活性组装的构象变化。突变分析揭示了一个保守的色氨酸，对于环化是必需的。我们表明，3'cADPR 是细菌抗病毒防御系统称为 Thoeris 的 ThsA 效应蛋白的激活剂，并且当由效应物 HopAM1 产生时，它是植物免疫的抑制剂。总的来说，我们的结果揭示了 cADPR 异构体产生的分子基础，并在细菌中确立了 3'cADPR 作为抗病毒和抑制植物免疫的信号分子。
