期刊论文详细信息
Functional complementation between FADD and RIP1 in embryos and lymphocytes
Article
关键词: RECEPTOR-INTERACTING PROTEIN;    DEATH DOMAIN PROTEIN;    CELL-DEATH;    KINASE RIP;    PROGRAMMED NECROSIS;    FAS;    APOPTOSIS;    REGULATOR;    FAS/APO1;   
DOI  :  10.1038/nature09878
来源: SCIE
【 摘 要 】

FADD is a common adaptor shared by several death receptors for signalling apoptosis through recruitment and activation of caspase 8 (refs 1-3). Death receptors are essential for immune homeostasis, but dispensable during embryogenesis. Surprisingly, Fadd(-/-) mice die in utero(4,5) and conditional deletion of FADD leads to impaired lymphocyte proliferation(6,7). How FADD regulates embryogenesis and lymphocyte responses has been a long-standing enigma. FADD could directly bind to RIP1 (also known as RIPK1), a serine/threonine kinase that mediates both necrosis and NF-kappa B activation. Here we show that Fadd(-/-) embryos contain raised levels of RIP1 and exhibit massive necrosis. To investigate a potential in vivo functional interaction between RIP1 and FADD, null alleles of RIP1 were crossed into Fadd(-/-) mice. Notably, RIP1 deficiency allowed normal embryogenesis of Fadd(-/-) mice. Conversely, the developmental defect of Rip1(-/-) lymphocytes was partially corrected by FADD deletion. Furthermore, RIP1 deficiency fully restored normal proliferation in Fadd(-/-) T cells but not in Fadd(-/-) B cells. Fadd(-/-)Rip1(-/-) double-knockout T cells are resistant to death induced by Fas or TNF-alpha and show reduced NF-kappa B activity. Therefore, our data demonstrate an unexpected cell-type-specific interplay between FADD and RIP1, which is critical for the regulation of apoptosis and necrosis during embryogenesis and lymphocyte function.

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