Martin, S.J., Henry, C.M. & Cullen, S.P. A perspective on mammalian caspases as positive and negative regulators of inflammation. Mol. Cell 46, 387-397

Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
Molecular cell (Impact Factor: 14.02). 05/2012; 46(4):387-97. DOI: 10.1016/j.molcel.2012.04.026
Source: PubMed


Members of the caspase family of cysteine proteases coordinate the morphological and biochemical events that typify apoptosis. However, neutralization of caspase activity in mammals fails to block death in response to most proapoptotic stimuli. This is because many cell death triggers provoke mitochondrial dysfunction upstream of caspase activation as a consequence of BAX/BAK channel opening. Although genetic or pharmacological inactivation of caspases fails to block cell death in most instances, it does convert the phenotype from apoptosis to necrosis. This has important implications for how the immune system responds to such cells, as necrotic cells provoke inflammation whereas apoptotic cells typically do not. Here, we propose an alternative perspective on apoptosis-associated caspase function by suggesting that these proteases are activated, not to kill, but to extinguish the proinflammatory properties of dying cells. This perspective unifies the mammalian caspase family as either positive or negative regulators of inflammation.

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Available from: Conor Henry, Jan 27, 2014
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    • "Bid activates Bax and Bak, which are located on the mitochondrial membrane, to trigger the release of cytochrome c (Scaffidi et al., 1998). Cells undergoing apoptosis ensure an anti-inflammatory response by the phagocytosing cell, resulting in the quiescent removal of dead and dying cells (Martin et al., 2012). Specific 'inflammatory caspases' belong to the caspase 1 family and are expressed in hematopoietic lineages (Schroder and Tschopp, 2012). "

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    • "It is now generally accepted that full-length IL-33 is biologically active upon release from damaged cells, but can undergo processing by certain neutrophil-derived proteases (see below) to amplify its activity. Processing of IL-33 by proapoptotic caspases might represent a mechanism to inactivate the pro-inflammatory activities of IL-33 during apoptosis (Martin et al., 2012). This is in contrast to necrotic caspase-independent cell death, which results in the release of active full-length IL-33 and activation of an inflammatory immune response (Figure 4). "
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    ABSTRACT: Members of the extended interleukin-1 (IL-1) cytokine family, such as IL-1, IL-18, IL-33, and IL-36, play a pivotal role in the initiation and amplification of immune responses. However, deregulated production and/or activation of these cytokines can lead to the development of multiple inflammatory disorders. IL-1 family members share a broadly similar domain organization and receptor signaling pathways. Another striking similarity between IL-1 family members is the requirement for proteolytic processing in order to unlock their full biological potential. Although much emphasis has been put on the role of caspase-1, another emerging theme is the involvement of neutrophil- and mast cell-derived proteases in IL-1 family cytokine processing. Elucidating the regulation of IL-1 family members by proteolytic processing is of great interest for understanding inflammation and immunity. Here, we review the identity of the proteases involved in the proteolytic processing of IL-1 family cytokines and the therapeutic implications in inflammatory disease. Copyright © 2015 Elsevier Inc. All rights reserved.
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    • "However , although Opa1 has been implicated in apoptosis-associated cristae junction remodeling, this event is not a major checkpoint in apoptosis and overexpression or knockdown of Opa1 does not greatly alter the threshold for apoptosis (Sheridan et al., 2008). Instead, it has been well established that members of the Bcl-2 family are the major determinants of cell survival in response to stresses that impact on the mitochondrial pathway to apoptosis (Martin et al., 2012). Thus, how Parkin influences cell-death decisions requires further clarification. "
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    ABSTRACT: Mitochondrial depolarization promotes Parkin- and PTEN-induced kinase 1 (PINK1)-dependent polyubiquitination of multiple proteins on mitochondrial outer membranes, resulting in the removal of defective mitochondria via mitophagy. Because Parkin mutations occur in Parkinson's disease, a condition associated with the death of dopaminergic neurons in the midbrain, wild-type Parkin is thought to promote neuronal survival. However, here we show that wild-type Parkin greatly sensitized toward apoptosis induced by mitochondrial depolarization but not by proapoptotic stimuli that failed to activate Parkin. Parkin-dependent apoptosis required PINK1 and was efficiently blocked by prosurvival members of the Bcl-2 family or knockdown of Bax and Bak. Upon mitochondrial depolarization, the Bcl-2 family member Mcl-1 underwent rapid Parkin- and PINK1-dependent polyubiquitination and degradation, which sensitized toward apoptosis via opening of the Bax/Bak channel. These data suggest that similar to other sensors of cell stress, such as p53, Parkin has cytoprotective (mitophagy) or cytotoxic modes (apoptosis), depending on the degree of mitochondrial damage. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Nov 2014 · Cell Reports
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