Members of the mammalian inflammatory caspase family, including caspase‐1, caspase‐4, caspase‐5, caspase‐11, and caspase‐12, are key regulators of the innate immune response. Most studies to date ...have focused on the role of caspase‐1 in the maturation of the proinflammatory cytokine interleukin‐1β and its upstream regulation by the inflammasome signaling complexes. However, an emerging body of research has supported a role for caspase‐4, caspase‐5, and caspase‐11 in both regulating caspase‐1 activation and inducing the inflammatory form of cell death called pyroptosis. This inflammatory caspase pathway appears essential for the regulation of cytokine processing. Consequently, insight into this noncanonical pathway may reveal important and, to date, understudied targets for the treatment of autoinflammatory disorders where the inflammasome pathway is dysregulated. Here, we will discuss the mechanisms of inflammasome and inflammatory caspase activation and how these pathways intersect to promote pathogen clearance.
The inflammatory caspases are key regulators of the innate immune response. Caspase‐1 is activated by the inflammasome signaling complexes to cleave the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18, while caspases‐4, ‐5, and ‐11 induce an inflammatory form of cell death called pyroptosis that is important for cytokine release. This review discusses the mechanisms of inflammasome and inflammatory caspase activation and how these pathways intersect to promote pathogen clearance.
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zVAD‐fmk is a widely used pan‐caspase inhibitor that blocks apoptosis but has undesirable side effects, including autophagy. In this issue, Needs et al. propose that zVAD‐fmk induces autophagy by ...inhibiting the N‐glycanase NGLY1 rather than caspases. NGLY1 is essential for the ERAD response and patients with inactivating mutations in NGLY1 present with neurodevelopmental defects and organ dysfunction. The ability of NGLY1 to inhibit basal levels of autophagy may contribute to this pathology. This study demonstrates possible crosstalk between protein turnover and autophagy while also underscoring the importance of specificity when using chemical tools to interrogate these pathways.
Comment on https://doi.org/10.1111/febs.16345
zVAD‐fmk is a pan‐caspase inhibitor that blocks apoptosis and also induces autophagy in some contexts. Needs et al. propose that zVAD‐fmk induces autophagy by inhibiting the N‐glycanase NGLY1. A different pan‐caspase inhibitor, qVD‐OPh, with a more highly selective warhead, does not inhibit NGLY1. This report underscores the importance of specificity when using chemical inhibitors to interrogate apoptosis and autophagy pathways.
Comment on https://doi.org/10.1111/febs.16345
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Removal of polyploid cells is essential to preventing cancer and restricting tumor growth. A new study published in The EMBO Journal shows assembly of the NEMO-PIDDosome on extra centrioles. ...Activation of this protein complex leads to NF-κB activation that, in turn, induces NK cell-mediated cell clearance.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
4.
Targeting apoptotic caspases in cancer Boice, Ashley; Bouchier-Hayes, Lisa
Biochimica et biophysica acta. Molecular cell research,
06/2020, Volume:
1867, Issue:
6
Journal Article
Peer reviewed
Open access
Members of the caspase family of proteases play essential roles in the initiation and execution of apoptosis. These caspases are divided into two groups: the initiator caspases (caspase-2, -8, -9 and ...-10), which are the first to be activated in response to a signal, and the executioner caspases (caspase-3, -6, and -7) that carry out the demolition phase of apoptosis. Many conventional cancer therapies induce apoptosis to remove the cancer cell by engaging these caspases indirectly. Newer therapeutic applications have been designed, including those that specifically activate individual caspases using gene therapy approaches and small molecules that repress natural inhibitors of caspases already present in the cell. For such approaches to have maximal clinical efficacy, emerging insights into non-apoptotic roles of these caspases need to be considered. This review will discuss the roles of caspases as safeguards against cancer in the context of the advantages and potential limitations of targeting apoptotic caspases for the treatment of cancer.
•The caspase family of proteases are essential to initiate and execute apoptotic cell death.•Deregulation of caspase expression and activation contributes to cancer and resistance to cancer therapies.•Targeting caspase pathways by gene therapy or endogenous inhibitors represents a promising therapeutic strategy for cancer.•Many caspases have non-apoptotic functions that need to be considered when targeting caspase pathways in cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
During apoptosis, the BCL-2 protein family controls mitochondrial outer membrane permeabilization (MOMP), but the dynamics of this regulation remain controversial. We employed chimeric proteins ...composed of exogenous BH3 domains inserted into a tBID backbone that can activate the proapoptotic effectors BAX and BAK to permeabilize membranes without being universally sequestered by all antiapoptotic BCL-2 proteins. We thus identified two “modes” whereby prosurvival BCL-2 proteins can block MOMP, by sequestering direct-activator BH3-only proteins (“MODE 1”) or by binding active BAX and BAK (“MODE 2”). Notably, we found that MODE 1 sequestration is less efficient and more easily derepressed to promote MOMP than MODE 2. Further, MODE 2 sequestration prevents mitochondrial fusion. We provide a unified model of BCL-2 family function that helps to explain otherwise paradoxical observations relating to MOMP, apoptosis, and mitochondrial dynamics.
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► BCL-2-like proteins sequester BH3-only proteins (MODE 1) or active BAX/BAK (MODE 2) ► Inhibition of apoptosis by MODE 1 is less efficient than that of MODE 2 ► MODE 1 and MODE 2 are sequentially engaged to block apoptosis in stressed cells ► Sequestration modes affect mitochondrial dynamics and sensitivity to derepression
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During apoptosis, the mitochondrial outer membrane is permeabilized, leading to the release of cytochrome c that activates downstream caspases. Mitochondrial outer membrane permeabilization (MOMP) ...has historically been thought to occur synchronously and completely throughout a cell, leading to rapid caspase activation and apoptosis. Using a new imaging approach, we demonstrate that MOMP is not an all-or-nothing event. Rather, we find that a minority of mitochondria can undergo MOMP in a stress-regulated manner, a phenomenon we term “minority MOMP.” Crucially, minority MOMP leads to limited caspase activation, which is insufficient to trigger cell death. Instead, this caspase activity leads to DNA damage that, in turn, promotes genomic instability, cellular transformation, and tumorigenesis. Our data demonstrate that, in contrast to its well-established tumor suppressor function, apoptosis also has oncogenic potential that is regulated by the extent of MOMP. These findings have important implications for oncogenesis following either physiological or therapeutic engagement of apoptosis.
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•MOMP can occur in a minority of mitochondria•Minority MOMP triggers caspase activity but fails to kill cells•Minority MOMP-induced caspase activity causes DNA damage and genomic instability•Minority MOMP promotes cellular transformation and tumorigenesis
During apoptosis, mitochondrial outer membrane permeabilization (MOMP) is widespread, leading to rapid cell death. Here, Ichim et al. demonstrate that MOMP can also be engaged in a minority of mitochondria without killing the cell. Instead, minority MOMP triggers caspase-dependent DNA damage and genomic instability, thereby promoting transformation and tumorigenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Using a Bax-dependent membrane-permeabilization assay, we show that peptides corresponding to the BH3 domains of Bcl-2 family “BH3-only” proteins have dual functions. Several BH3 peptides relieved ...the inhibition of Bax caused by the antiapoptotic Bcl-x
L and/or Mcl-1 proteins, some displaying a specificity for either Bcl-x
L or Mcl-1. Besides having this derepression function, the Bid and Bim peptides activated Bax directly and were the only BH3 peptides tested that could potently induce cytochrome c release from mitochondria in cultured cells. Furthermore, Bax activator molecules (cleaved Bid protein and the Bim BH3 peptide) synergistically induced cytochrome c release when introduced into cells along with derepressor BH3 peptides. These observations support a unified model of BH3 domain function, encompassing both positive and negative regulation of other Bcl-2 family members. In this model, the simple inhibition of antiapoptotic functions is insufficient to induce apoptosis unless a direct activator of Bax or Bak is present.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Members of the caspase family are well known for their roles in the initiation and execution of cell death. Due to their function in the removal of damaged cells that could otherwise become ...malignant, caspases are important players in the DNA damage response (DDR), a network of pathways that prevent genomic instability. However, emerging evidence of caspases positively or negatively impacting the accumulation of DNA damage in the absence of cell death demonstrates that caspases play a role in the DDR that is independent of their role in apoptosis. This review highlights the apoptotic and non-apoptotic roles of caspases in the DDR and how they can impact genomic stability and cancer treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The tumor suppressor p53 exerts its anti-neoplastic activity primarily through the induction of apoptosis. We found that cytosolic localization of endogenous wild-type or trans-activation-deficient ...p53 was necessary and sufficient for apoptosis. p53 directly activated the proapoptotic Bcl-2 protein Bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program. p53 also released both proapoptotic multidomain proteins and BH3-only proteins Proapoptotic Bcl-2 family proteins that share only the third Bcl-2 homology domain (BH3) that were sequestered by Bcl-xL. The transcription-independent activation of Bax by p53 occurred with similar kinetics and concentrations to those produced by activated Bid. We propose that when p53 accumulates in the cytosol, it can function analogously to the BH3-only subset of proapoptotic Bcl-2 proteins to activate Bax and trigger apoptosis.
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The Trp53 tumor suppressor gene product (p53) functions in the nucleus to regulate proapoptotic genes, whereas cytoplasmic p53 directly activates proapoptotic Bcl-2 proteins to permeabilize ...mitochondria and initiate apoptosis. Here, we demonstrate that a tripartite nexus between Bcl-xL, cytoplasmic p53, and PUMA coordinates these distinct p53 functions. After genotoxic stress, Bcl-xL sequestered cytoplasmic p53. Nuclear p53 caused expression of PUMA, which then displaced p53 from Bcl-xL, allowing p53 to induce mitochondrial permeabilization. Mutant Bcl-xL that bound p53, but not PUMA, rendered cells resistant to p53-induced apoptosis irrespective of PUMA expression. Thus, PUMA couples the nuclear and cytoplasmic proapoptotic functions of p53.
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