Caspase-1 and Caspase-8 Cleave and Inactivate Cellular Parkin

Kahns, Søren; Kalai, Michaël; Jakobsen, Lene Diness; Clark, Brian F. C.; Vandenabeele, Peter; Jensen, Poul Henning

doi:10.1074/jbc.m300495200

Cited by 70 publications

(50 citation statements)

References 47 publications

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“…To identify the mechanisms by which inflammasomes block mitophagy, we addressed the role of Parkin, a central mitophagy regulator. Parkin is recruited to damaged mitochondria, allowing for ubiquitination of mitochondrial proteins and targeting to the mitophagy pathway (22), and was shown to be cleaved by Caspase-1 (24). Using a 293T cell reconstitution system, we showed that the AIM2 inflammasome cleaves Parkin and that this cleavage required Caspase-1 catalytic activity because it was ablated in cells expressing Caspase-1 C284A (Fig.…”

Section: Inflammasomes Mediate Parkin Cleavage and Inhibit Mitophagymentioning

confidence: 97%

Inflammasome activation leads to Caspase-1–dependent mitochondrial damage and block of mitophagy

Nagasu

Murakami

et al. 2014

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

410

332

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Inflammasomes are intracellular sensors that couple detection of pathogens and cellular stress to activation of Caspase-1, and consequent IL-1β and IL-18 maturation and pyroptotic cell death. Here, we show that the absent in melanoma 2 (AIM2) and nucleotidebinding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasomes trigger Caspase-1-dependent mitochondrial damage. Caspase-1 activates multiple pathways to precipitate mitochondrial disassembly, resulting in mitochondrial reactive oxygen species (ROS) production, dissipation of mitochondrial membrane potential, mitochondrial permeabilization, and fragmentation of the mitochondrial network. Moreover, Caspase-1 inhibits mitophagy to amplify mitochondrial damage, mediated in part by cleavage of the key mitophagy regulator Parkin. In the absence of Parkin activity, increased mitochondrial damage augments pyroptosis, as indicated by enhanced plasma membrane permeabilization and release of danger-associated molecular patterns (DAMPs). Therefore, like other initiator caspases, Caspase-1 activation by inflammasomes results in mitochondrial damage.inflammasomes | mitochondrial damage | pyroptosis | mitophagy

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Section: Inflammasomes Mediate Parkin Cleavage and Inhibit Mitophagymentioning

confidence: 97%

Inflammasome activation leads to Caspase-1–dependent mitochondrial damage and block of mitophagy

Nagasu

Murakami

et al. 2014

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

410

332

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“…Thus, presenilins (54,55) and ␤-amyloid precursor protein (56 -60) undergo caspase-derived cleavages, generating proteolytic fragments controlling cell death. More related to PD, parkin, another binding partner of synphilin-1 (18,61) displaying an antiapoptotic phenotype (62,63), is also cleaved by caspases, but unlike for synphilin-1, this endoproteolysis leads to a loss of function of this protein (64).…”

Section: Discussionmentioning

confidence: 99%

Caspase-3-derived C-terminal Product of Synphilin-1 Displays Antiapoptotic Function via Modulation of the p53-dependent Cell Death Pathway

Giaime

Sunyach

Grosso³

et al. 2006

Journal of Biological Chemistry

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Parkinson disease is the second most frequent neurodegenerative disorder after Alzheimer disease. A subset of genetic forms of Parkinson disease has been attributed to ␣-synuclein, a synaptic protein with remarkable chaperone properties. Synphilin-1 is a cytoplasmic protein that has been identified as a partner of ␣-synuclein (Engelender, S., Kaminsky, Z., Guo, X., Sharp, A. H., Amaravi, R. K., Kleiderlein, J. J., Margolis, R. L., Troncoso, J. C., Lanahan, A. A., Worley, P. F., Dawson, V. L., Dawson, T. M., and Ross, C. A. (1999) Nat. Gen. 22, 110 -114), but its function remains totally unknown. We show here for the first time that synphilin-1 displays an antiapoptotic function in the control of cell death. We have established transient and stable transfectants overexpressing wild-type synphilin-1 in human embryonic kidney 293 cells, telecephalon-specific murine 1 neurons, and SH-SY5Y neuroblastoma cells, and we show that both cell systems display lower responsiveness to staurosporine and 6-hydroxydopamine. Thus, synphilin-1 reduces procaspase-3 hydrolysis and thereby caspase-3 activity and decreases poly(ADPribose) polymerase cleavage, two main indicators of apoptotic cell death. Furthermore, we establish that synphilin-1 drastically reduces p53 transcriptional activity and expression and lowers p53 promoter transactivation and mRNA levels. Interestingly, we demonstrate that synphilin-1 catabolism is enhanced by staurosporine and blocked by caspase-3 inhibitors. Accordingly, we show by transcription/translation assay that recombinant caspase-3 and, to a lesser extent, caspase-6 but not caspase-7 hydrolyze synphilin-1. Furthermore, we demonstrate that mutated synphilin-1, in which a consensus caspase-3 target sequence has been disrupted, resists proteolysis by cellular and recombinant caspases and displays drastically reduced antiapoptotic phenotype. We further show that the caspase-3-derived C-terminal fragment of synphilin-1 was probably responsible for the antiapoptotic phenotype elicited by the parent wild-type protein. Altogether, our study is the first demonstration that synphilin-1 harbors a protective function that is controlled by the C-terminal fragment generated by its proteolysis by caspase-3.Parkinson disease (PD) 3 is characterized by the presence of intracytoplasmic inclusions, named Lewy bodies (LB), and by a massive loss of dopaminergic neurons in the substantia nigra (2). Most PD cases are of sporadic origin, but about 15% are associated with genetic causes. From the various loci associated with PD, named PARKs, six proteins have been identified so far. They are linked to either autosomal dominant (␣-synuclein, UCHL1, and LRRK2/dardarin) or autosomal recessive (parkin, DJ-1, and PINK-1) transmission (3-5), the latter forms being more severe and characterized by an early onset. The above proteins are linked to the three major dysfunctions observed in PD, which are oxidative stress, mitochondrial failure, and proteasomal dysfunction (6). Interestingly, these dysfunctions are associated with exa...

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“…Caspase cleavage of parkin may also contribute to the pathology of PD in sporadic forms of the disease. 110,111 In spite of the strong evidence suggesting that caspase activity is an integral component of the neurotoxicity observed in a number of chronic neurodegenerative diseases, there is at least some suggestive evidence that the sustained cell stress in chronic degenerative diseases may lead to enhanced survival to acute stressors, an adaptation that may be akin to preconditioning cells. Indeed, mice expressing exon 1 of the human Huntington gene are resistant to intrastriatal injections of quinolinate, dopamine or 6-hydroxydopamine112.…”

Section: Ramification Of Use Of Caspase Inhibitors In Neurological DImentioning

confidence: 99%

The kinder side of killer proteases: Caspase activation contributes to neuroprotection and CNS remodeling

McLaughlin

2004

Apoptosis

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Caspases are a family of cysteine proteases that are expressed as inactive zymogens and undergo proteolytic maturation in a sequential manner in which initiator caspases cleave and activate the effector caspases 3, 6 and 7. Effector caspases cleave structural proteins, signaling molecules, DNA repair enzymes and proteins which inhibit apoptosis. Activation of effector, or executioner, caspases has historically been viewed as a terminal event in the process of programmed cell death. Emerging evidence now suggests a broader role for activated caspases in cellular maturation, differentiation and other non-lethal events. The importance of activated caspases in normal cell development and signaling has recently been extended to the CNS where these proteases have been shown to contribute to axon guidance, synaptic plasticity and neuroprotection. This review will focus on the adaptive roles activated caspases in maintaining viability, the mechanisms by which caspases are held in check so as not produce apoptotic cell death and the ramifications of these observations in the treatment of neurological disorders.

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Caspase-1 and Caspase-8 Cleave and Inactivate Cellular Parkin

Cited by 70 publications

References 47 publications

Inflammasome activation leads to Caspase-1–dependent mitochondrial damage and block of mitophagy

Inflammasome activation leads to Caspase-1–dependent mitochondrial damage and block of mitophagy

Caspase-3-derived C-terminal Product of Synphilin-1 Displays Antiapoptotic Function via Modulation of the p53-dependent Cell Death Pathway

The kinder side of killer proteases: Caspase activation contributes to neuroprotection and CNS remodeling

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