Caspases and Kinases in a Death Grip

Kurokawa, Manabu; Kornbluth, Sally

doi:10.1016/j.cell.2009.08.021

Cited by 409 publications

(372 citation statements)

References 139 publications

(187 reference statements)

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“…Apoptosis is mediated by proteases called caspases, which are activated in response to extracellular signals or upon intracellular stresses (reviewed in refs. [1][2][3][4][5][6][7][8][9][10][11][12]. Apoptosis involves the activation of initiator caspases (e.g., caspase-8).…”

mentioning

confidence: 99%

The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments

Piatkov

Brower

Varshavsky

2012

Proc. Natl. Acad. Sci. U.S.A.

126

195

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In the course of apoptosis, activated caspases cleave ∼500 to ∼1,000 different proteins in a mammalian cell. The dynamics of apoptosis involve a number of previously identified, caspase-generated proapoptotic protein fragments, defined as those that increase the probability of apoptosis. In contrast to activated caspases, which can be counteracted by inhibitor of apoptosis proteins, there is little understanding of antiapoptotic responses to proapoptotic protein fragments. One possibility is the regulation of proapoptotic fragments through their selective degradation. The previously identified proapoptotic fragments Cys-RIPK1, Cys-TRAF1, Asp-BRCA1, Leu-LIMK1, Tyr-NEDD9, Arg-BID, Asp-BCL XL , Arg-BIM EL , Asp-EPHA4, and Tyr-MET bear destabilizing N-terminal residues. Tellingly, the destabilizing nature (but not necessarily the actual identity) of N-terminal residues of proapoptotic fragments was invariably conserved in evolution. Here, we show that these proapoptotic fragments are short-lived substrates of the Arg/N-end rule pathway. Metabolic stabilization of at least one such fragment, Cys-RIPK1, greatly augmented the activation of the apoptosis-inducing effector caspase-3. In agreement with this understanding, even a partial ablation of the Arg/N-end rule pathway in two specific N-end rule mutants is shown to sensitize cells to apoptosis. We also found that caspases can inactivate components of the Arg/N-end rule pathway, suggesting a mutual suppression between this pathway and proapoptotic signaling. Together, these results identify a mechanistically specific and functionally broad antiapoptotic role of the Arg/N-end rule pathway. In conjunction with other apoptosis-suppressing circuits, the Arg/N-end rule pathway contributes to thresholds that prevent a transient or otherwise weak proapoptotic signal from reaching the point of commitment to apoptosis.

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mentioning

confidence: 99%

The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments

Piatkov

Brower

Varshavsky

2012

Proc. Natl. Acad. Sci. U.S.A.

126

195

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“…The apoptosis pathway is regulated by the actions of a series of caspases [27]. Caspase-3, caspase-8, and caspase-9 were significantly activated in PPRV-infected EECs compared with mock-infected EECs at 96 hpi but not at 72 hpi (Figure 10(a-f)).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, there is an extremely complex interaction between autophagy and invading viruses. In contrast, apoptosis is regulated by CASPs/caspases, which are apoptosis-related cysteine peptidases [27,28]. Two main signals induce apoptosis, namely, the intrinsic and extrinsic pathways.…”

Section: Introductionmentioning

confidence: 99%

“…Two main signals induce apoptosis, namely, the intrinsic and extrinsic pathways. The induction of the intrinsic pathway results in mitochondrial outer membrane permeabilization, thus triggering CASP3/caspase-3 by activating CASP9/caspase-9 [27]. The extrinsic pathway activates CASP3 via CASP8/caspase-8 cleavage in a death receptor-mediated manner [27].…”

Section: Introductionmentioning

confidence: 99%

“…The induction of the intrinsic pathway results in mitochondrial outer membrane permeabilization, thus triggering CASP3/caspase-3 by activating CASP9/caspase-9 [27]. The extrinsic pathway activates CASP3 via CASP8/caspase-8 cleavage in a death receptor-mediated manner [27]. Apoptosis could also be considered a defence mechanism against virus replication because it triggers cell death [29].…”

Section: Introductionmentioning

confidence: 99%

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Autophagy enhances the replication of Peste des petits ruminants virus and inhibits caspase-dependent apoptosis in vitro

Yang

Xue

et al. 2018

Virulence

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Peste des petits ruminants (PPR) is an acute and highly contagious disease in small ruminants that causes significant economic losses in developing countries. An increasing number of studies have demonstrated that both autophagy and apoptosis are important cellular mechanisms for maintaining homeostasis, and they participate in the host response to pathogens. However, the crosstalk between apoptosis and autophagy in host cells during PPRV infection has not been clarified. In this study, autophagy was induced upon virus infection in caprine endometrial epithelial cells (EECs), as determined by the appearance of double- and single-membrane autophagy-like vesicles, LC3-I/LC3-II conversion, and p62 degradation. We also found that PPRV infection triggered a complete autophagic response, most likely mediated by the non-structural protein C and nucleoprotein N. Moreover, our results suggest that autophagy not only promotes the replication of PPRV in EECs but also provides a potential mechanism for inhibiting PPRV-induced apoptosis. Inhibiting autophagosome formation by wortmannin and knocking down the essential autophagic proteins Beclin-1 and ATG7 induces caspase-dependent apoptosis in EECs in PPRV infection. However, inhibiting autophagosome and lysosome fusion by NH4Cl and chloroquine did not increase the number of apoptotic cells. Collectively, these data are the first to indicate that PPRV-induced autophagy inhibits caspase-dependent apoptosis and thus contributes to the enhancement of viral replication and maturity in host cells.

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RNA Regulation in Apoptosis

Roretz

Gallouzi

2013

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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Caspases and Kinases in a Death Grip

Cited by 409 publications

References 139 publications

The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments

The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments

Autophagy enhances the replication of Peste des petits ruminants virus and inhibits caspase-dependent apoptosis in vitro

RNA Regulation in Apoptosis

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