Functional complementation between FADD and RIP1 in embryos and lymphocytes

Abstract

SummaryFADD 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.

RIP kinases: key decision makers in cell death and innate immunity

“…This is consistent with the developmental lethality, due to cardiac failure, in FADDdeficient embryos, 72 with RIP1 deficiency rescuing the embryonic lethality associated with FADD deficiency. 71 These studies support a model in which the FADD-caspase 8-c-FLIP complex negatively regulates RIP-kinase-mediated necrosis. This raises the apparent paradox of c-FLIP interacting with caspase 8 to facilitate caspase-mediated processing of RIP kinases while c-FLIP also serves to inhibit caspase 8 in the apoptotic pathway.…”

Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis

“…[5][6][7] Physiological function of necroptosis has been illustrated in host defense, [8][9][10][11] inflammation, [12][13][14][15][16] tissue injury, 10,17,18 and development. [19][20][21] Necroptosis can be induced by a number of different extracellular stimuli such as tumor necrosis factor (TNF). TNF stimulation leads to formation of TNF receptor 1 (TNFR1) signaling complex (named complex I), and complex II containing RIP1, TRADD, FAS-associated protein with a death domain (FADD), and caspase-8, of which the activation initiates apoptosis.…”

New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy

“…A marked increase in T-cell numbers was also observed in RIP1-and FADD-double knockout chimaeras (Zhang et al, 2011), suggesting that a hyper-proliferative disorder can occur when components of necroptosis signalling are altered. Furthermore, the truncated splice variant of RIP3, RIP3g, has been reported to be upregulated in cancer tissues (Yang et al, 2005).…”

“…The formation of complex II initiates the cell death signal and the decision between death via apoptosis or necroptosis is determined at this step. Caspase-8-mediated cleavage of RIP1 and RIP3 will trigger the caspase cascade and induce apoptosis (Lin et al, 1999), whereas the inhibition of caspase-8 (by zVAD-fmk, CrmA or cFLIP L ) or knockout of FADD will abrogate the apoptotic signal to favour necroptosis (Holler et al, 2000;Cho et al, 2009b;Zhang et al, 2011). Recently, O'Donnell et al (2011) reported caspase-8 to also cleave CYLD, preventing the deubiquitylation of RIP1 and thereby, necroptosis.…”

“…The physiological relevance of necroptosis has been a common debate since its discovery because the phenomenon is usually observed only upon pharmacologic (zVAD-fmk) or genetic (Apaf-1 or FADD knockout) inhibition of the apoptotic pathway (Shiraishi et al, 2010;Wu et al, 2011;Zhang et al, 2011). This apparent overshadowing of necroptosis by apoptosis implies that apoptotic death is the first choice in most settings and that necroptosis acts only as a safeguard alternative to ensure cell demise is inevitable should the apoptotic machinery fail.…”