PDF(Pubmed)
Abstract：
Protein ADP-ribosylation plays important but ill-defined roles in antiviral signalling cascades such as the interferon response. Several viruses of clinical interest, including coronaviruses, express hydrolases that reverse ADP-ribosylation catalysed by host enzymes, suggesting an important role for this modification in host-pathogen interactions. However, which ADP-ribosyltransferases mediate host ADP-ribosylation, what proteins and pathways they target and how these modifications affect viral infection and pathogenesis is currently unclear. Here we show that host ADP-ribosyltransferase activity induced by IFNγ signalling depends on PARP14 catalytic activity and that the PARP9/DTX3L complex is required to uphold PARP14 protein levels via post-translational mechanisms. Both the PARP9/DTX3L complex and PARP14 localise to IFNγ-induced cytoplasmic inclusions containing ADP-ribosylated proteins, and both PARP14 itself and DTX3L are likely targets of PARP14 ADP-ribosylation. We provide evidence that these modifications are hydrolysed by the SARS-CoV-2 Nsp3 macrodomain, shedding light on the intricate cross-regulation between IFN-induced ADP-ribosyltransferases and the potential roles of the coronavirus macrodomain in counteracting their activity.
摘要：
蛋白质ADP-核糖基化在抗病毒信号级联如干扰素应答中起着重要但不明确的作用。几种临床感兴趣的病毒，包括冠状病毒,表达由宿主酶催化的逆转ADP核糖基化的水解酶，提示这种修饰在宿主-病原体相互作用中的重要作用。然而,其中ADP-核糖基转移酶介导宿主ADP-核糖基化，它们靶向的蛋白质和途径以及这些修饰如何影响病毒感染和发病机制目前尚不清楚。在这里，我们表明由IFNγ信号诱导的宿主ADP-核糖基转移酶活性取决于PARP14催化活性，并且PARP9/DTX3L复合物需要通过翻译后机制维持PARP14蛋白水平。PARP9/DTX3L复合物和PARP14均位于IFNγ诱导的含有ADP核糖基化蛋白的细胞质包涵体，PARP14本身和DTX3L都可能是PARP14ADP核糖基化的靶标。我们提供的证据表明，这些修饰被SARS-CoV-2Nsp3宏域水解，揭示了IFN诱导的ADP-核糖基转移酶之间复杂的交叉调节以及冠状病毒宏观结构域在抵消其活性中的潜在作用。
