Functional complementation between FADD and RIP1 in embryos and lymphocytes.

Published

Journal Article

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 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.

Full Text

Duke Authors

Cited Authors

  • Zhang, H; Zhou, X; McQuade, T; Li, J; Chan, FK-M; Zhang, J

Published Date

  • March 17, 2011

Published In

Volume / Issue

  • 471 / 7338

Start / End Page

  • 373 - 376

PubMed ID

  • 21368761

Pubmed Central ID

  • 21368761

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

Digital Object Identifier (DOI)

  • 10.1038/nature09878

Language

  • eng

Conference Location

  • England