FLIPL permits apoptotic and inflammatory signaling and inhibits necroptosis in mice without Caspase-8 oligomerization

• 成果类型: Article
• 署名作者: Shaw, Jeremy J. P.; Guy, Cliff; Tummers, Bart; Green, Douglas R.
• 署名单位: St Jude Children's Research Hospital; University of London; King's College London
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13146
• DOI: 10.1073/pnas.2415992122
• 发表日期: 2025-04-15
• 关键词: c-flip; death; switch; fadd; modulation; RESISTANT; inducers

摘要

Caspase- 8 signaling has proapoptotic, antinecroptotic, and proinflammatory signaling roles dependent on interaction with the adapter molecule FADD, oligomerization, and autocleavage. Previously, a Caspase- 8 binding partner cFLIPL (FLIP, encoded by Cflar) was shown to prevent Caspase- 8- dependent apoptosis, but permit Caspase- 8- dependent inhibition of necroptosis. We sought to explore the role of FLIP in Caspase- 8- dependent apoptosis induction, necroptosis inhibition, and inflammatory signaling inhibition in vitro and in vivo. We provide evidence that in mice with a mutation that prevents promote apoptosis, regulate inflammation, and control lymphoproliferative disease. but ablation of Mlkl, required for necroptosis, allows their survival to adulthood. Further, oproliferative disease. We analyzed apoptosis, necroptosis, and inflammatory signaling in Casp8FGLG/FGLG mice with or without FLIP, gaining insights into the functions of the Caspase- 8-FLIP heterodimer in vitro and in vivo.