Functional complementation between FADD and RIP1 in embryos and lymphocytes

H Zhang, X Zhou, T McQuade, J Li, FKM Chan, J Zhang - Nature, 2011 - nature.com
H Zhang, X Zhou, T McQuade, J Li, FKM Chan, J Zhang
Nature, 2011nature.com
FADD is a common adaptor shared by several death receptors for signalling apoptosis
through recruitment and activation of caspase 8 (refs). Death receptors are essential for
immune homeostasis, but dispensable during embryogenesis. Surprisingly, Fadd−/− mice
die in utero, and conditional deletion of FADD leads to impaired lymphocyte proliferation,.
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 …
Abstract
FADD is a common adaptor shared by several death receptors for signalling apoptosis through recruitment and activation of caspase 8 (refs ). Death receptors are essential for immune homeostasis, but dispensable during embryogenesis. Surprisingly, Fadd−/− mice die in utero, and conditional deletion of FADD leads to impaired lymphocyte proliferation,. 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-κB 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-α and show reduced NF-κB 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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