C-Abl-mediated tyrosine phosphorylation of PARP1 is crucial for expression of proinflammatory genes

Ameer Ali Bohio, Aman Sattout, Ruoxi Wang, Ke Wang, Rajiv Kumar Sah, Xiaolan Guo, Xianlu Zeng, Yueshuang Ke, Istvan Boldogh, Xueqing Ba

Research output: Contribution to journalArticle

Abstract

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-α 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-κB-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.

Original languageEnglish (US)
Pages (from-to)1521-1531
Number of pages11
JournalJournal of Immunology
Volume203
Issue number6
DOIs
StatePublished - Sep 15 2019

    Fingerprint

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Bohio, A. A., Sattout, A., Wang, R., Wang, K., Sah, R. K., Guo, X., Zeng, X., Ke, Y., Boldogh, I., & Ba, X. (2019). C-Abl-mediated tyrosine phosphorylation of PARP1 is crucial for expression of proinflammatory genes. Journal of Immunology, 203(6), 1521-1531. https://doi.org/10.4049/jimmunol.1801616