Work

Faculty Opinions recommendation of Functional complementation between FADD and RIP1 in embryos and lymphocytes.

Year: 2011

Type: peer-review

Abstract: FADD is a common adaptor shared by several death-receptors (DRs) for signaling apoptosis through recruitment and activation of caspase 81-3.DRs are essential for immune homeostasis, but dispensable during embryogenesis.Surprisingly, FADD -/-mice die in utero4-5 and conditional deletion of FADD leads to impaired lymphocyte proliferation6-7.How FADD regulates embryogenesis and lymphocyte responses has been a long standing enigma.FADD could directly bind to RIP1, a serine/threonine kinase which mediates both necrosis and NF-κB activation.Here we show that FADD -/-embryos contain elevated levels of RIP1 and exhibit massive necrosis.To investigate potential in vivo functional interaction between RIP1 and FADD, null alleles of RIP1 were crossed into FADD -/-mice.Strikingly, 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 (DKO) T cells are resistant to death induced by Fas or TNFα and display 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.Programmed cell death (PCD) including apoptosis and necrosis are fundamental biological processes that are essential during embryonic development and for homeostasis in somatic tissues.DRs can signal apoptotic cell death when engaged by their cognate ligands8.This extrinsic death pathway requires the adaptor protein FADD that couples the signal generated Users may view, print,

Source: Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

DOI: 10.3410/f.8887956.10219054

Authors: Hao Wu, Jixi Li

Institutions: Boston Children's Hospital, Harvard University, Thomas Jefferson University, Sidney Kimmel Cancer Center

Language: English

Topic: Cell death mechanisms and regulation

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: Concern Foundation, National Institutes of Health