A viral necrosome mediates direct RIPK3 activation to promote inflammatory necroptosis

• 成果类型: Article
• 署名作者: Li, Shufen; Li, Hao; Zhou, Zhenxing; Ye, Meidi; Wang, Yifei; Li, Wenqin; Guan, Zhenqiong; Guan, Zihan; Zhang, Chongtao; Zhang, Yulan; Liu, Wei; Peng, Ke
• 署名单位: Chinese Academy of Sciences; Wuhan Institute of Virology, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Academy of Military Medical Sciences - China
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12219
• DOI: 10.1073/pnas.2420245122
• 发表日期: 2025-05-27
• 关键词: liquid phase-separation; mixed lineage kinase; cell-death; programmed necrosis; signaling proteins; severe fever; virus; interferon; inhibition; phosphorylation

摘要

Necroptosis is an inflammatory programmed cell death pathway triggered by RIPK3 activation through one of the upstream RHIM-domain-containing proteins including RIPK1, TRIF, and ZBP1. Whether necroptosis can be activated independent of the upstream signaling pathways leading to inflammatory pathogenesis remains ambiguous. Here, we revealed a mechanism in which a viral protein mediates direct RIPK3 activation resulting in severe inflammatory pathogenesis in patients. The nonstructural protein NSs of a pathogenic hemorrhagic virus, SFTSV, interacts with the RIPK3 kinase domain and forms biocondensate to promote RIPK3 autophosphorylation and necroptosis activation in an RHIM-independent manner. In parallel, sequestration of RIPK3 within the NSs-RIPK3 condensate inhibited RIPK3-mediated apoptosis and promoted viral replication. Infection with an SFTSV NSs mutant virus not forming NSs condensate triggered pronounced apoptosis resulting in reduced viral replication and decreased fatality in vivo. Blocking SFTSV-triggered necroptosis through depletion of MLKL or treatment with a RIPK3-kinase inhibitor reduced viral inflammatory pathogenesis and fatality in vivo. In contrast, blocking SFTSV-triggered apoptosis through depletion of RIPK3 resulted in enhanced viral replication and increased fatality in vivo. The virus-triggered necroptosis correlated with severe inflammatory pathogenesis and lethality in virus-infected patients. The NSs-RIPK3 condensate may represent a necroptosis activation mechanism that promotes viral pathogenesis.