Nitric Oxide Negatively Regulates Fas CD95-induced Apoptosis through Inhibition of Ubiquitin-Proteasome-mediated Degradation of FLICE Inhibitory Protein

Chanvorachote, Pithi; Nimmannit, Ubonthip; Wang, Liying; Stehlik, Christian; Lü, Bin; Azad, Neelam; Rojanasakul, Yon

doi:10.1074/jbc.m510080200

Cited by 97 publications

(87 citation statements)

References 64 publications

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“…c-FLIP has been shown to be ubiquitinated and degraded via the proteasome (63,(65)(66)(67)(68)(69). In light of our previous study, showing that the ubiquitin-proteasome pathway is a crucial determinant for the c-FLIP S protein levels (63), a likely mechanism for the hyperthermia-induced down-regulation of c-FLIP is increased proteasomal degradation.…”

Section: Discussionmentioning

confidence: 92%

“…Several studies showing that c-FLIP is degraded via the ubiquitinproteasome pathway (63,(65)(66)(67)(68)(69), prompted us to examine whether proteasomal degradation of c-FLIP was enhanced upon hyperthermia. Indeed, the hyperthermia-induced down-regulation of c-FLIP was inhibited in Jurkat cells pretreated with the specific proteasome inhibitor epoxomicin (Fig.…”

Section: Hyperthermia Enhances Ubiquitination and Proteasomal Degradamentioning

confidence: 99%

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Fever-Like Hyperthermia Controls T Lymphocyte Persistence by Inducing Degradation of Cellular FLIPshort

Meinander

Söderström

Kaunisto

et al. 2007

The Journal of Immunology

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Fever has a major impact on immune responses by modulating survival, proliferation, and endurance of lymphocytes. Lymphocyte persistence in turn is determined by the equilibrium between death and survival-promoting factors that regulate death receptor signaling in these cells. A potential integrator of death receptor signaling is the caspase-8 inhibitor c-FLIP, the expression of which is dynamically regulated, either rapidly induced or down-regulated. In this study, we show in activated primary human T lymphocytes that hyperthermia corresponding to fever triggered down-regulation of both c-FLIP-splicing variants, c-FLIPshort (c-FLIPS) and c-FLIPlong, with consequent sensitization to apoptosis mediated by CD95 (Fas/APO-1). The c-FLIP down-regulation and subsequent sensitization was specific for hyperthermic stress. Additionally, we show that the hyperthermia-mediated down-regulation was due to increased ubiquitination and proteasomal degradation of c-FLIPS, the stability of which we have shown to be regulated by its C-terminal splicing tail. Furthermore, the induced sensitivity to CD95 ligation was independent of heat shock protein 70, as thermotolerant cells, expressing substantially elevated levels of heat shock protein 70, were not rescued from the effect of hyperthermia-mediated c-FLIP down-regulation. Our findings indicate that fever significantly influences the rate of lymphocyte elimination through depletion of c-FLIPS. Such a general regulatory mechanism for lymphocyte removal has broad ramifications for fever-mediated regulation of immune responses.

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Section: Discussionmentioning

confidence: 92%

Section: Hyperthermia Enhances Ubiquitination and Proteasomal Degradamentioning

confidence: 99%

Fever-Like Hyperthermia Controls T Lymphocyte Persistence by Inducing Degradation of Cellular FLIPshort

Meinander

Söderström

Kaunisto

et al. 2007

The Journal of Immunology

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“…Studies in human bronchial epithelial cell lines have led to the proposal that nitric oxide, which can be regulated by Akt, 33 also can prevent FLIP L degradation induced by Fas. 34 Further work will allow identification of the signaling mechanism by which Akt prevents FLIP L degradation. Moreover, determining to what extent this mechanism is used in other cell types such as motor neurons, which are also sensitive to Fas, will be interesting.…”

Section: Discussionmentioning

confidence: 99%

Met signals hepatocyte survival by preventing Fas-triggered FLIP degradation in a PI3k-Akt-dependent manner

et al. 2007

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“…Indeed, in the presence of CHX, the rapid degradation of S193A mutant led to a more pronounced to the particular needs of a cell. c-FLIP is regulated by a variety of posttranslational modifications, such as nitrosylation 23 and ubiquitylation. 19,24,25 Our previous studies have shown that ubiquitylation-mediated isoform-specific regulation of c-FLIP stability is vital for death receptor responses upon erythroid differentiation and lymphocyte persistence during hyperthermia.…”

Section: Phosphorylation Of C-flip By Pkcmentioning

confidence: 99%

PKC-mediated phosphorylation regulates c-FLIP ubiquitylation and stability

et al. 2009

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Cellular FLICE-inhibitory protein (c-FLIP) proteins are crucial regulators of the death-inducing signaling complex (DISC) and caspase-8 activation. To date, three c-FLIP isoforms with distinct functions and regulation have been identified. Our previous studies have shown that the stability of c-FLIP proteins is subject to isoform-specific regulation, but the underlying molecular mechanisms have not been known. Here, we identify serine 193 as a novel in vivo phosphorylation site of all c-FLIP proteins and demonstrate that S193 phosphorylation selectively influences the stability of the short c-FLIP isoforms, as S193D mutation inhibits the ubiquitylation and selectively prolongs the half-lives of c-FLIP short (c-FLIP S ) and c-FLIP Raji (c-FLIP R ). S193 phosphorylation also decreases the ubiquitylation of c-FLIP long (c-FLIP L ) but, surprisingly, does not affect its stability, indicating that S193 phosphorylation has a different function in c-FLIP L . The phosphorylation of this residue is operated by the protein kinase C (PKC), as S193 phosphorylation is markedly increased by treatment with 12-O-tetradecanoylphorbol-13-acetate and decreased by inhibition of PKCa and PKCb. S193 mutations do not affect the ability of c-FLIP to bind to the DISC, although S193 phosphorylation is increased by death receptor stimulation. Instead, S193 phosphorylation affects the intracellular level of c-FLIP S , which then determines the sensitivity to death-receptor-mediated apoptosis. These results reveal that the differential stability of c-FLIP proteins is regulated in an isoform-specific manner by PKC-mediated phosphorylation.

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Nitric Oxide Negatively Regulates Fas CD95-induced Apoptosis through Inhibition of Ubiquitin-Proteasome-mediated Degradation of FLICE Inhibitory Protein

Cited by 97 publications

References 64 publications

Fever-Like Hyperthermia Controls T Lymphocyte Persistence by Inducing Degradation of Cellular FLIPshort

Fever-Like Hyperthermia Controls T Lymphocyte Persistence by Inducing Degradation of Cellular FLIPshort

Met signals hepatocyte survival by preventing Fas-triggered FLIP degradation in a PI3k-Akt-dependent manner

PKC-mediated phosphorylation regulates c-FLIP ubiquitylation and stability

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