c-Abl-Mediated Tyrosine Phosphorylation of PARP1 Is Crucial for Expression of Proinflammatory Genes
c-Abl-Mediated Tyrosine Phosphorylation of PARP1 Is Crucial for Expression of Proinflammatory Genes
复制标题
c-Abl 介导的 PARP1 酪氨酸磷酸化对于促炎基因的表达至关重要
DOI：
10.4049/jimmunol.1801616
复制
发表时间：
2019-09-15
影响因子：
4.4
通讯作者：
Ba, Xueqing
中科院分区：
文献类型：
--
作者：
Bohio, Ameer Ali;Sattout, Aman;Ba, Xueqing
聚ADP核糖基化是一种快速、短暂的蛋白质翻译后修饰，主要由聚ADP核糖聚合酶1（PARP 1）催化。活化的PARP 1在DNA损伤修复和细胞反应途径中的基本作用已得到充分确立;然而，PARP 1独立于DNA损伤而被活化的确切机制，从而在炎症基因的表达中发挥作用，仍然知之甚少。在这项研究中，我们表明，在响应LPS或TNF-α暴露，非受体酪氨酸激酶c-Abl进行核转位和相互作用，并磷酸化PARP 1在保守的Y829位点。酪氨酸磷酸化的PARP 1是小鼠RAW 264.7巨噬细胞、人单核细胞THP 1细胞或小鼠肺中RelA/p65的蛋白质聚（ADP-核糖基）化和促炎基因的NF-κ B依赖性表达所必需的。此外，通过抑制c-Abl活性，LPS诱导的气道肺炎症减少。本研究阐明了一种新的激活PARP 1和调节基因表达的信号通路，表明阻断c-Abl与PARP 1的相互作用或药物抑制c-Abl可能改善PARP 1激活介导的炎症性疾病的结果。
Poly(ADP-ribosyl)ation is a rapid and transient posttranslational protein modification mostly catalyzed by poly(ADP-ribose) polymerase-1 (PARP1). Fundamental roles of activated PARP1 in DNA damage repair and cellular response pathways are well established; however, the precise mechanisms by which PARP1 is activated independent of DNA damage, and thereby playing a role in expression of inflammatory genes, remain poorly understood. In this study, we show that, in response to LPS or TNF-alpha exposure, the nonreceptor tyrosine kinase c-Abl undergoes nuclear translocation and interacts with and phosphorylates PARP1 at the conserved Y829 site. Tyrosine-phosphorylated PARP1 is required for protein poly(ADP-ribosyl)ation of RelA/p65 and NF-kappa B-dependent expression of proinflammatory genes in murine RAW 264.7 macrophages, human monocytic THP1 cells, or mouse lungs. Furthermore, LPS-induced airway lung inflammation was reduced by inhibition of c-Abl activity. The present study elucidated a novel signaling pathway to activate PARP1 and regulate gene expression, suggesting that blocking the interaction of c-Abl with PARP1 or pharmaceutical inhibition of c-Abl may improve the outcomes of PARP1 activation-mediated inflammatory diseases.