Activation of death-inducing signaling complex (DISC) by pro-apoptotic C-terminal fragment of RIP

Kim, Jin Woo; Choi, Eui Ju; Joe, Cheol O.

doi:10.1038/sj.onc.1203796

Cited by 93 publications

(75 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Dimerized RIPK3 gyrase can activate caspase 8 (but not detectably in L929 cells) and lead to processing of downstream caspases and PARP, and it does so more efficiently in the presence of RIPK1 requirement for caspase-dependent apoptosis is controversial. 6,31,35 To test whether the kinase activity of RIPK3 was required for either form of RIPK3 gyrase-induced death, we initially generated a K51A kinase-dead mutant of the RIPK3 gyrase vector. 9 We expressed it in WT MEFs, immunoprecipitated the RIPK3 gyrase and confirmed that the kinase was inactive in an in vitro assay (Figure 7a).…”

Section: Resultsmentioning

confidence: 99%

RIPK1- and RIPK3-induced cell death mode is determined by target availability

et al. 2014

View full text Add to dashboard Cite

Both receptor-interacting protein kinase 1 (RIPK1) and RIPK3 can signal cell death following death receptor ligation. To study the requirements for RIPK-triggered cell death in the absence of death receptor signaling, we engineered inducible versions of RIPK1 and RIPK3 that can be activated by dimerization with the antibiotic coumermycin. In the absence of TNF or other death ligands, expression and dimerization of RIPK1 was sufficient to cause cell death by caspase-or RIPK3-dependent mechanisms. Dimerized RIPK3 induced cell death by an MLKL-dependent mechanism but, surprisingly, also induced death mediated by FADD, caspase 8 and RIPK1. Catalytically active RIPK3 kinase domains were essential for MLKL-dependent but not for caspase 8-dependent death. When RIPK1 or RIPK3 proteins were dimerized, the mode of cell death was determined by the availability of downstream molecules such as FADD, caspase 8 and MLKL. These observations imply that rather than a 'switch' operating between the two modes of cell death, the final mechanism depends on levels of the respective signaling and effector proteins. Mammalian cells can use a number of mechanisms to kill themselves. The best characterized depends on the Bcl-2 family members Bax and Bak that work via mitochondria to activate caspases. 1 Some caspases, notably caspase 8, can be activated independently of Bcl-2 family members, for example, after stimulation of members of the TNF receptor superfamily. 2 Recently, it has become apparent that some of these receptors, including TNFR1, can activate a third suicide mechanism that does not require caspases, and in which the morphology of the dying cell differs from classical apoptosis. This form of cell death, termed 'necroptosis', can often be blocked by necrostatin-1 (nec-1), an inhibitor of the kinase activity of receptor-interacting protein kinase 1 (RIPK1). 3,4 Accordingly, observations from several groups have shown that in some cell types, expression of RIPK1 can signal cell death by caspase-independent necroptosis. 5 It has previously been revealed that RIPK1 could function downstream of death receptors, but in those cases, cell death was usually blocked by coexpression of the viral inhibitor of caspases 1 and 8, CrmA, 6 and typically exhibited a classical 'apoptotic' morphology. It was revealed that RIPK1 engages FADD via homotypic binding of their death domains (DDs), and FADD in turn activates caspase 8. 6,7 RIPK3, like RIPK1, bears a kinase domain and RIP homology interaction motif (RHIM), but unlike RIPK1 does not have a DD. 8-11 RIPK3 is required for necroptosis. 12,13 Furthermore, RIPK1 appears to activate RIPK3 in this pathway, as cell death could be blocked by nec-1. 14 RIPK3 activates, by phosphorylation, MLKL, a pseudokinase essential for this death pathway. [15][16][17] Once activated, MLKL forms multimers that trigger breaches of the plasma membrane. [18][19][20] Although RIPK3 is necessary for necroptosis, it is unclear whether activation of RIPK3 is sufficient for cell death, because TNF activates signaling ...

show abstract

Section: Resultsmentioning

confidence: 99%

RIPK1- and RIPK3-induced cell death mode is determined by target availability

et al. 2014

View full text Add to dashboard Cite

show abstract

“…RIP1 has been shown to initiate a caspase-independent mechanism for Fas-mediated cell death in T cells when co-expressed with FADD [97]. In addition, Cellular Signalling 15 (2003) 983 -992 PubMed ID: 14499341 caspase 8-mediated cleavage of RIP1 produces a C-terminal fragment that appears to enhance apoptosis through enhanced DISC formation [98]. RIP1 belongs to a family with at least three other members that include RIP2 [99, 100 and 101], RIP3 [102 and 103] and RIP4 [104].…”

Section: Cellular Signalling 15 (2003) 983 -992 Pubmed Id: 14499341mentioning

confidence: 99%

Live and let die: regulatory mechanisms in Fas-mediated apoptosis

Curtin

Cotter

2003

Cellular Signalling

172

140

View full text Add to dashboard Cite

“…123 #1. Cys-RIPK1 is the proapoptotic Ct fragment of the RIPK1 kinase, a regulator of apoptosis, necroptosis, and other processes, including antiviral responses that do not involve cell death 178,[181][182][183] [see also Fig. 6(A)].…”

Section: Protein Fragments Their Generation Despite Deleterious Effementioning

confidence: 99%

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

View full text Add to dashboard Cite

Despite extensive understanding of sleep regulation, the molecular-level cause and function of sleep are unknown. I suggest that they originate in individual neurons and stem from increased production of protein fragments during wakefulness. These fragments are transient parts of protein complexes in which the fragments were generated. Neuronal Ca 21 fluxes are higher during wakefulness than during sleep. Subunits of transmembrane channels and other proteins are cleaved by Ca 21 -activated calpains and by other nonprocessive proteases, including caspases and secretases. In the proposed concept, termed the fragment generation (FG) hypothesis, sleep is a state during which the production of fragments is decreased (owing to lower Ca 21 transients) while fragment-destroying pathways are upregulated. These changes facilitate the elimination of fragments and the remodeling of protein complexes in which the fragments resided. The FG hypothesis posits that a proteolytic cleavage, which produces two fragments, can have both deleterious effects and fitness-increasing functions. This (previously not considered) dichotomy can explain both the conservation of cleavage sites in proteins and the evolutionary persistence of sleep, because sleep would counteract deleterious aspects of protein fragments. The FG hypothesis leads to new explanations of sleep phenomena, including a longer sleep after sleep deprivation. Studies in the 1970s showed that ethanol-induced sleep in mice can be strikingly prolonged by intracerebroventricular injections of either Ca 21 alone or Ca 21 and its ionophore (Erickson et al., Science 1978;199:1219-1221 Harris, Pharmacol Biochem Behav 1979;10:527-534; Erickson et al., Pharmacol Biochem Behav 1980;12:651-656). These results, which were never interpreted in connection to protein fragments or the function of sleep, may be accounted for by the FG hypothesis about molecular causation of sleep.

show abstract

Activation of death-inducing signaling complex (DISC) by pro-apoptotic C-terminal fragment of RIP

Cited by 93 publications

References 38 publications

RIPK1- and RIPK3-induced cell death mode is determined by target availability

RIPK1- and RIPK3-induced cell death mode is determined by target availability

Live and let die: regulatory mechanisms in Fas-mediated apoptosis

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Contact Info

Product

Resources

About