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Related Concept Videos

Caspases01:24

Caspases

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Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside...
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The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

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The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
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The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

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Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
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The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

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Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
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Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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The Unfolded Protein Response01:37

The Unfolded Protein Response

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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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Caspase-4 dimerisation and D289 auto-processing elicit an interleukin-1β-converting enzyme.

Amy H Chan1, Sabrina S Burgener1, Kassandra Vezyrgiannis2

  • 1Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, St Lucia, Australia.

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The noncanonical inflammasome uses caspase-4 to defend against bacteria. Caspase-4 activation and self-cleavage lead to cell death and direct IL-1β maturation, independent of the NLRP3 inflammasome.

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • The noncanonical inflammasome is crucial for cellular defense against Gram-negative bacteria.
  • Caspase-4 activation within this complex is essential for initiating inflammatory responses.
  • The precise mechanisms of caspase-4 activation and substrate cleavage were previously unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms governing caspase-4 activation and proteolytic activity.
  • To identify the substrates and signaling pathways regulated by caspase-4.
  • To understand the role of caspase-4 in inflammasome-mediated immunity.

Main Methods:

  • Investigated caspase-4 dimerization and self-cleavage using biochemical assays.
  • Analyzed the proteolytic activity of caspase-4 species.
  • Examined caspase-4-mediated cleavage of gasdermin-D (GSDMD) and pro-IL-1β in human myeloid and epithelial cells.

Main Results:

  • Caspase-4 dimerizes and undergoes self-cleavage at D270 and D289 to become fully active.
  • Self-cleavage at D289 generates a p34/p9 caspase-4 species.
  • This active caspase-4 species directly cleaves pro-IL-1β, independent of the NLRP3 inflammasome, leading to IL-1β maturation and secretion.

Conclusions:

  • Caspase-4 activation involves dimerization and specific self-cleavage events.
  • Caspase-4 directly processes pro-IL-1β, revealing a novel inflammasome-independent IL-1β maturation pathway.
  • This study clarifies key molecular events in noncanonical inflammasome signaling and identifies IL-1β as a direct caspase-4 substrate.