PARP12-mediated mono-ADP-ribosylation as a checkpoint for necroptosis and apoptosis

• 成果类型: Article
• 署名作者: Huang, Xin; Li, Fangxia; Liu, Lin; Li, Yanxia; Zhang, Mengmeng; Ma, Guoming; Gao, Ying; Shan, Bing; Liang, Xiaozhen; Yuan, Junying; Pan, Heling
• 署名单位: Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; Shanghai Institute of Immunity and Infection, CAS
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10785
• DOI: 10.1073/pnas.2426660122
• 发表日期: 2025-06-17
• 关键词: mixed lineage kinase; programmed necrosis; cell-death; mediated apoptosis; rip1 kinase; protein; parps; phosphorylation; identification; inflammation

摘要

Necroptosis and apoptosis are two alternatively regulated cell death pathways. Activation of RIPK1 upon engagement of TNFR1 by TNF alpha may promote necroptosis by interacting with RIPK3 or apoptosis by activating caspases. RIPK1 is extensively regulated by a variety of dynamic posttranslational modifications which control its kinase activity and formation of downstream complexes to mediate necroptosis and apoptosis. Here, we investigate the functional significance and mechanism by which PARP12, a mono-ADP-ribosyltransferase, interacts with RIPK1 and RIPK3 in cells stimulated by IFN gamma and TNF alpha. We show that PARP12 catalyzes the mono-ADP-ribosylation (MARylation) of RIPK1 in both the intermediate domain and the kinase domain, as well as the MARylation of RIPK3. PARP12 deficiency reduces necroptosis by inhibiting the activation of RIPK1 kinase and its interaction with RIPK3, as well as sensitizes to apoptosis by promoting the binding of RIPK1 with caspase-8. Thus, upon induction by IFNs, PARP12 may function as a cellular checkpoint that controls RIPK1 to promote necroptosis and inhibit apoptosis. Importantly, while PARP12 is a known interferon-stimulated gene (ISG), PARP12 deficiency promotes the expression of a subset of ISGs and confers protection against influenza A virus-induced mortality in mice. Our study demonstrates that PARP12 is an important modulator of cellular antiviral response.