Alternative titles; symbols
HGNC Approved Gene Symbol: CASP4
Cytogenetic location: 11q22.3 Genomic coordinates (GRCh38): 11:104,942,866-104,968,574 (from NCBI)
Accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and triggers an unfolded protein response (UPR) involving inhibition of protein synthesis, elevated expression of ER protein-folding chaperones, and/or apoptosis. CASP4 is involved in UPR-dependent apoptosis via activation of a caspase cascade (Moorwood and Barton, 2014).
The mouse Casp11 gene is most homologous to human CASP4. In addition, the mouse Casp12 gene (608633) encodes a protein that may be functionally equivalent to human CASP4. In most humans, CASP12 is an inactive pseudogene. See 608633 for information on mouse and human CASP12.
Cysteine proteases related to mammalian interleukin-1-beta converting enzyme (ICE, or CASP1; 147678) and nematode CED3 have been implicated in apoptotic cell death. By screening a human thymus cDNA library with the human ICE coding sequence, Kamens et al. (1995) isolated cDNAs encoding CASP4, which they called ICH2. The 377-amino acid ICH2 protein shares 53% amino acid identity with ICE and contains the residues conserved in all ICE family members. By Northern blot analysis, ICH2 was expressed as an approximately 1.7-kb transcript in all tissues examined except brain.
Munday et al. (1995) isolated a cDNA encoding CASP4, called ICE(rel)II by them, from a human monocyte cDNA library. Structural motifs similar to those in ICE suggested that ICE(rel)II is synthesized as a proenzyme that is proteolytically processed to form a heterodimeric active enzyme.
Faucheu et al. (1995) used RT-PCR and anchor-PCR to clone a cDNA encoding CASP4, which they called TX.
Hitomi et al. (2004) noted that rodent Casp12 has been implicated in ER stress-induced apoptosis and amyloid-beta (see 104760)-induced apoptosis, but that human CASP12 is nonfunctional. By screening a human colon cDNA library with mouse Casp12, they identified CASP4 as a putative functional ortholog of Casp12. Human CASP4 shares 48% homology with mouse Casp12. Immunofluorescence microscopy, immunoelectron microscopy, and biochemical fractionation showed that CASP4 localized predominantly to ER, and additionally to mitochondria, in HeLa cells and SK-N-SH human neuroblastoma cells.
Kamens et al. (1995) determined that the CASP4 gene contains 8 coding exons.
Kamens et al. (1995) mapped the CASP4 gene to a P1 clone containing the ICE gene, which is located at chromosome 11q22.2-q22.3.
Kamens et al. (1995) found that ICH2 and ICE shared catalytic properties but differed in substrate specificities, suggesting that the 2 enzymes have different functions in vivo. Overexpression of ICH2 in insect cells induced apoptosis.
Munday et al. (1995) found that ICE(rel)II proteins lacking the pro-domain were capable of effectively inducing fibroblast apoptosis.
Transfection experiments by Faucheu et al. (1995) demonstrated that TX functioned as a protease that could cleave the ICE precursor and its own precursor. However, TX could not generate mature interleukin-1-beta (IL1B; 147720) from pro-IL1B.
Hitomi et al. (2004) found that treatment of human SK-N-SH cells with ER stress-inducing reagents, but not other apoptotic reagents, resulted in CASP4 cleavage. Administration of neurotoxic amyloid-beta also resulted in CASP4 cleavage. Overexpression of BCL2 in SK-N-SH cells or HeLa cells did not affect CASP4 cleavage, suggesting that CASP4 is primarily activated in ER stress-induced apoptosis. Reduction of CASP4 expression via small interfering RNA decreased ER stress-induced and amyloid-beta-induced apoptosis, but not ER stress-independent apoptosis, in HeLa cells and SK-N-SH cells. Hitomi et al. (2004) concluded that CASP4 is an ER stress-specific caspase that may function similarly to mouse Casp12.
Using microarray analysis, Kajiwara et al. (2009) showed that FE65 (APBB1; 602709) and TSHZ3 (614119) downregulated expression of CASP4. Knockdown of either FE65 or TSHZ3 via small interfering RNA increased CASP4 expression, and knockdown of both increased CASP4 expression in an additive manner. Chromatin immunoprecipitation analysis confirmed that both FE65 and TSHZ3 associated with the CASP4 promoter. In postmortem Alzheimer disease (AD; 104300) brains, expression of FE65 and teashirt proteins, particularly TSHZ3, was inversely correlated with expression of CASP4. FE65 and teashirt expression was reduced, whereas CASP4 expression was elevated, with severity of AD as measured by cognitive impairment, plaque density, and neurofibrillary involvement.
Using mouse strains lacking genes involved in inflammasome activation, Rathinam et al. (2012) showed that endotoxin of Gram-negative bacteria interacted with Tlr4 (603030), followed by interaction of this complex with Trif (TICAM1; 607601), expression of and signaling by Ifnb (147640), and ultimately expression of Casp11, which is most homologous to human CASP4. Casp11 then worked together with the assembled Nlrp3 (606416) inflammasome to activate Casp1, leading to Il1b and Il18 (600953) secretion and Casp1-independent cell death. This pathway was not engaged by Gram-positive bacteria. Rathinam et al. (2012) concluded that TLRs are master regulators of inflammasome signaling, particularly during Gram-negative bacterial infection-induced septic shock.
Using Western blot analysis, Sollberger et al. (2012) observed secretion of CASP4 by primary human keratinocytes upon ultraviolet B irradiation. Knockdown of CASP4 or CASP1 with small interfering RNA resulted in reduced expression of IL1B. CASP4 function required the NLRP3 inflammasome, and CASP4 physically interacted with CASP1. Sollberger et al. (2012) concluded that CASP4 has an important role in inflammation and innate immunity through the activation of CASP1.
Miao et al. (2011) reviewed pyroptosis, a mechanism of cell death distinct from apoptosis and oncosis/necrosis. Both pyroptosis and apoptosis are programmed cell death mechanisms, but they are dependent on different caspases, unlike oncosis. Similar to oncosis and unlike apoptosis, pyroptosis results in cellular lysis and release of cytosolic contents to the extracellular space, inducing inflammation and the release of IL1B and IL18. Aachoui et al. (2013) noted that both Casp1 and Casp11 trigger pyroptosis. Using Burkholderia thailandensis, which is related to but less virulent than B. pseudomallei, the gram-negative bacteria that cause melioidosis, as well as cytosolic mutants of Legionella pneumophila and Salmonella typhimurium, which normally reside in vacuoles, Aachoui et al. (2013) showed in mouse macrophages and mice that Casp11 mediated innate immunity to cytosolic, but not vacuolar, bacteria. Triggering of Casp11 and induction of pyroptosis did not require inflammasome pathways involving Nlrp3, Nlrc4 (606831), Aim2 (604578), or Asc (PYCARD; 606838), nor did they require production of Il1b or Il18. Casp11 was required to protect mice from lethal challenge with either B. thailandensis or B. pseudomallei. Aachoui et al. (2013) concluded that Casp11 mediates pyroptosis and protects mice from lethal infection by bacteria that have the ability to invade the cytosol.
Li et al. (2013) found that knockdown of TMEM214 (615301) significantly inhibited apoptosis induced by the endoplasmic reticulum (ER) stress inducers thapsigargin and brefeldin A. Coimmunoprecipitation and colocalization experiments indicated that TMEM214 constitutively associated with procaspase-4 in human cells in the presence or absence of these ER stress inducers. Knockdown of either procaspase-4 or TMEM214 abrogated ER stress-induced apoptosis, and knockdown of TMEM214 alone dramatically reduced the association of procaspase-4 with the ER. Li et al. (2013) concluded that TMEM214 anchors procaspase-4 to the outer ER membrane and that this interaction is required for ER stress-induced apoptosis.
In mice, gram-negative bacteria, including E. coli, C. rodentium, S. typhimurium, and S. flexneri, are sensed by an intracellular inflammasome complex that activates Casp11. Kayagaki et al. (2013) showed that macrophages loaded with synthetic lipid A, E. coli lipopolysaccharide (LPS), or S. typhimurium LPS activate Casp11 independently of the LPS receptor Tlr4. Consistent with lipid A triggering the noncanonical inflammasome, LPS containing a divergent lipid A structure antagonized CASP11 activation in response to E. coli LPS or gram-negative bacteria. Moreover, LPS-mutant E. coli failed to activate Casp11. Tlr4-null mice primed with Tlr3 (603029) agonist polyinosinic:polycytidylic acid to induce pro-Casp11 expression were as susceptible as wildtype mice to sepsis induced by E. coli LPS. Kayagaki et al. (2013) concluded that the data unveiled a TLR4-independent mechanism for innate immune recognition of LPS.
Hagar et al. (2013) reported that contamination of cytoplasm by LPS is the signal that triggers Casp11 activation in mice. Specifically, Casp11 responds to penta- and hexa-acylated lipid A, whereas tetra-acylated lipid A is not detected, providing a mechanism of evasion for cytosol-invasive Francisella. Priming the Casp11 pathway in vivo resulted in extreme sensitivity to subsequent LPS challenge in both wildtype and Tlr4-deficient mice, whereas Casp11-deficient mice were relatively resistant. Hagar et al. (2013) concluded that their data revealed a novel pathway for detecting cytoplasmic LPS.
Meunier et al. (2014) reported that a cluster of small interferon-inducible GTPases, the so-called guanylate-binding proteins, is required for the full activity of the noncanonical mouse Casp11 (human CASP4) inflammasome during infections with vacuolar gram-negative bacteria. Meunier et al. (2014) showed that guanylate-binding proteins are recruited to intracellular bacterial pathogens and are necessary to induce the lysis of the pathogen-containing vacuole. Lysis of the vacuole releases bacteria into the cytosol, thus allowing the detection of their LPS by a sensor. Moreover, recognition of the lysed vacuole by the danger sensor galectin-8 (LGALS8; 606099) initiates the uptake of bacteria into autophagosomes, which results in a reduction of Casp11 activation. Meunier et al. (2014) concluded that host-mediated lysis of pathogen-containing vacuoles is an essential immune function and is necessary for efficient recognition of pathogens by inflammasome complexes in the cytosol.
Using genomewide CRISPR-Cas9 nuclease screens of Casp11- and Casp1 (147678)-mediated pyroptosis in mouse bone marrow macrophages, Shi et al. (2015) identified Gsdmd (617042). Cells lacking Gsdmd resisted induction of pyroptosis by cytosolic LPS and inflammasome ligands and showed limited release of Il1b. CASP1, CASP4, CASP5, or Casp11 specifically cleaved the linker between the N-terminal and C-terminal GSDMD domains, and this cleavage was necessary and sufficient for pyroptosis. Inflammatory caspases did not cleave other gasdermin family members. Shi et al. (2015) concluded that pyroptosis is gasdermin-mediated programmed necrosis.
Kayagaki et al. (2015) showed that Gsdmd was essential for Casp11-dependent pyroptosis and Il1b maturation in mice. Mice lacking Gsdmd exhibited defective pyroptosis and Il1b secretion induced by cytoplasmic LPS or gram-negative bacteria. Gsdmd -/- mice were protected from lethal doses of LPS. Casp11 cleaved Gsdmd, and the resulting N-terminal fragment promoted pyroptosis and Nlrp3-dependent activation of Casp1. Kayagaki et al. (2015) concluded that Gsdmd is a critical target of Casp11 and a key mediator of the host response against gram-negative bacteria.
The effects of LPS on TLR4-dependent inflammation can be promoted or inhibited by the oxidized phospholipid oxPAPC, a putative LPS mimic present in dying cells and damaged tissues. Zanoni et al. (2016) found that murine macrophages and dendritic cells (DCs) contained abundant viperin (RSAD2; 607810) and phosphorylated Stat1 (600555) and produced inflammatory cytokines after stimulation with LPS, but not oxPAPC, indicating that oxPAPC cannot activate Tlr4. Sequential stimulation with LPS and then oxPAPC induced hyperactivation of DCs, which in turn induced potent adaptive immune responses elicited by Casp11. Distinct domains of Casp11 bound LPS and oxPAPC. Both lipids induced Casp11-dependent Il1 release, but only LPS induced pyroptosis. Zanoni et al. (2016) proposed that cells and receptors of the innate immune system can achieve different activation states, permitting context-dependent responses to infection.
Using knockout mice, Mandal et al. (2018) showed that proapoptotic Casp8 and propyroptotic Casp11 were essential for lethal LPS shock and E. coli sepsis. Casp8 and Casp11 were not required for initiation of LPS shock, which was triggered by a distinct hematopoietic initiator compartment. Small intestine and spleen were the critical target organs affected by Casp8-dependent LPS shock. Casp8 and Casp11 dictated ileal inflammation and both contributed to LPS-driven systemic inflammation. However, neither Casp8 nor Casp11 was individually sufficient for shock, and both Casp8 and Casp11 had to collaborate to execute inflammatory tissue injury underlying endotoxemia. The collaboration was driven by Tnf and type I IFN for the execution of LPS shock, but it was independent of Ripk1 (603453) activity. Casp11 enhanced activation of Casp8, but Casp11-dependent pyroptosis was independent of Casp8.
Wang et al. (1998) reported the inactivation of mouse casp11, which is most homologous to human CASP4, by gene targeting. Like Ice-deficient mice, casp11 mutant mice are resistant to endotoxic shock induced by LPS. Production of both IL1-alpha and IL1-beta after LPS stimulation, a crucial event during septic shock and an indication of ICE activation, is blocked in casp11 mutant mice. Casp11 mutant embryonic fibroblast cells are resistant to apoptosis induced by overexpression of ICE. Furthermore, Wang et al. (1998) found that pro-caspase-11 physically interacts with pro-ICE in cells and that the expression of casp11 is essential for activation of ICE. The authors suggested that caspase-11 is a component of the ICE complex and is required for the activation of ICE.
Using C57BL/6 Casp11 -/- mice, Kayagaki et al. (2011) found that Casp11 was critical for Casp1 (147678) activation and Il1b production in bacteria-infected macrophages. The defect in Il1b production was recapitulated in strain-129 mice, which harbored a Casp11 mutation that attenuated Casp11 expression. Kayagaki et al. (2011) noted that strain-129 mice were used by Kuida et al. (1995) and Li et al. (1995) to generate Casp1 -/- mice, and consequently these mice lacked both Casp1 and Casp11. Casp11 -/- macrophages were able to produce normal levels of Il1b in response to ATP and monosodium urate. Strain-129 macrophages lacking Casp1 but expressing C57BL/6 Casp11 were unable to secrete Il1b normally in response to any stimulus, confirming that Casp1 is essential for Il1b production. However, Casp11, rather than Casp1, was required for noncanonical inflammasome-triggered macrophage cell death. Loss of Casp11, rather than Casp1, protected mice from a lethal dose of LPS. Kayagaki et al. (2011) concluded that there is a unique proinflammatory role for Casp11 in innate immune response to clinically significant bacterial infections.
Broz et al. (2012) demonstrated that noncanonical caspase-11 activation contributes to macrophage death during S. typhimurium infection. TLR4 (603030)-dependent and TIR domain-containing adaptor-inducing interferon-beta (TRIF)-dependent interferon-beta production is crucial for caspase-11 activation in macrophages, but is only partially required for procaspase-11 expression, consistent with the existence of an interferon-inducible activator of caspase-11. Furthermore, Casp1-null mice were significantly more susceptible to infection with S. typhimurium than mice lacking both proinflammatory caspases (Casp1-null/Casp11-null). This phenotype was accompanied by higher bacterial counts, the formation of extracellular bacterial microcolonies in the infected tissue, and a defect in neutrophil-mediated clearance. Broz et al. (2012) concluded that caspase-11-dependent cell death is detrimental to the host in the absence of caspase-1-mediated innate immunity, resulting in extracellular replication of a facultative intracellular bacterial pathogen.
Moorwood and Barton (2014) found cleaved CASP4 in muscle biopsies from Duchenne muscular dystrophy (DMD; 300377) patients, but not in healthy controls, suggesting ER stress and activation of the UPR. Expression of both the pro and cleaved forms of Casp12, the mouse equivalent of human CASP4, was also elevated in muscles in the mdx mouse model of DMD, concomitant with elevated markers of ER stress. Knockout of Casp12 in mdx mice tended to preserve muscle function compared with mdx muscle, with 75% recovery of specific force generation and resistance to eccentric contractions. Compensatory hypertrophy usually found in mdx muscle was normalized in the absence of Casp12, which was due to decreased fiber size rather than a shift in fiber type. Deletion of Casp12 did not reduce mdx muscle fibrosis or appearance. Muscle fiber degeneration in mdx mouse was reduced to almost wildtype levels in Casp12 -/- mdx muscle. Moorwood and Barton (2014) concluded that deletion of Casp12 promoted muscle fiber survival in mdx mice and that aberrant UPR activation may contribute to DMD pathogenesis in humans.
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