Poly(ADP-ribose) polymerase 7 (PARP-7) has emerged as a critically important member of a large enzyme family that catalyzes ADP-ribosylation in mammalian cells. PARP-7 is a critical regulator of the innate immune response. What remains unclear is the mechanism by which PARP-7 regulates this process, namely because the protein targets of PARP-7 mono-ADP-ribosylation (MARylation) are largely unknown. Here, we combine chemical genetics, proximity labeling, and proteome-wide amino acid ADP-ribosylation site profiling for identifying the direct targets and sites of PARP-7-mediated MARylation in a cellular context. We found that the inactive PARP family member, PARP-13-a critical regulator of the antiviral innate immune response-is a major target of PARP-7. PARP-13 is preferentially MARylated on cysteine residues in its RNA binding zinc finger domain. Proteome-wide ADP-ribosylation analysis reveals cysteine as a major MARylation acceptor of PARP-7. This study provides insight into PARP-7 targeting and MARylation site preference.

中文翻译：

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化学遗传学和全蛋白质组位点作图揭示了 PARP-7 对免疫相关蛋白靶点的半胱氨酸 MARylation

聚 (ADP-核糖) 聚合酶 7 (PARP-7) 已成为在哺乳动物细胞中催化 ADP-核糖基化的大型酶家族的重要成员。PARP-7 是先天免疫反应的关键调节因子。尚不清楚的是 PARP-7 调节这一过程的机制，即因为 PARP-7 单 ADP-核糖基化 (MARylation) 的蛋白质靶标在很大程度上是未知的。在这里，我们结合化学遗传学、邻近标记和蛋白质组范围的氨基酸 ADP 核糖基化位点分析来识别 PARP-7 介导的 MARylation 在细胞环境中的直接靶标和位点。我们发现非活性 PARP 家族成员 PARP-13（抗病毒先天免疫反应的关键调节因子）是 PARP-7 的主要靶标。PARP-13 在其 RNA 结合锌指结构域中的半胱氨酸残基上优先被 MARylated。蛋白质组范围的 ADP 核糖基化分析显示半胱氨酸是 PARP-7 的主要 MARylation 受体。这项研究提供了对 PARP-7 靶向和 MArylation 位点偏好的深入了解。