Abstract
Caspase-11 is a pro-inflammatory enzyme that is stringently regulated during its expression and activation. As caspase-11 is not constitutively expressed in cells, it requires a priming step for its upregulation, which occurs following the stimulation of pathogen and cytokine receptors. Once expressed, caspase-11 activation is triggered by its interaction with lipopolysaccharide (LPS) from Gram-negative bacteria. Being an initiator caspase, activated caspase-11 functions primarily through its cleavage of key substrates. Gasdermin D (GSDMD) is the primary substrate of caspase-11, and the GSDMD cleavage fragment generated is responsible for the inflammatory form of cell death, pyroptosis, via its formation of pores in the plasma membrane. Thus, caspase-11 functions as an intracellular sensor for LPS and an immune effector. This review provides an overview of caspase-11—describing its structure and the transcriptional mechanisms that govern its expression, in addition to its activation, which is reported to be regulated by factors such as guanylate-binding proteins (GBPs), high mobility group box 1 (HMGB1) protein, and oxidized phospholipids. We also discuss the functional outcomes of caspase-11 activation, which include the non-canonical inflammasome, modulation of actin dynamics, and the initiation of blood coagulation, highlighting the importance of inflammatory caspase-11 during infection and disease.
Highlights
Caspases are a family of cysteine aspartic proteases that have been classically subdivided into those involved in apoptosis or inflammation
IL-1β signals through the interleukin 1 receptor (IL-1R), resulting in the activation of NF-κB [36], we have shown that IL-1β-mediated upregulation of caspase-11 is impaired in Ifnar−/−
The phagocytosis of Gram-negative bacteria by innate immune cells such as macrophages results in caspase-11 activation, but additional studies demonstrated that caspase-11 dependent cell death was significantly impaired in bone marrow-derived macrophages (BMDMs) that were deficient for a group of IFN-inducible GTPases, guanylate-binding proteins found on chromosome 3 (GBPchro3 ), which encode for GBP1, GBP2, GBP3, GBP5 and GBP7, thereby implicating these GTPases in the controlled lysis of vacuoles containing Gram-negative bacteria [43,44]
Summary
Caspases are a family of cysteine aspartic proteases that have been classically subdivided into those involved in apoptosis or inflammation. The long pro-domains of inflammatory caspases consist of CARD protein interaction domains, while the protease domain consists of a large (20 kDa) and small (10 kDa) subunit that contains the catalytic cysteine residue. Caspase-1 was first identified as a pre-aspartate-specific protease involved in the cleavage of the pro-IL-1β (31 kDa) precursor to its biologically active form, IL-1β (17 kDa) [4]. IL-1β and IL-18 are potent proinflammatory cytokines that induce fever and IFNγ secretion, respectively Their production is tightly regulated, with both cytokines being synthesized as immature precursors that require caspase-1 mediated processing for their maturation. Caspase-1 is the prototypical member of the inflammatory caspase family, caspase-11 is emerging as an important inflammatory regulator, controlling the activation of the noncanonical inflammasome in addition to other effector functions, which will be discussed in this review
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