Caspase 11

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Caspase-11
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Murine caspase-11, and its human homologs caspase-4 and caspase-5, are mammalian intracellular receptor proteases activated by TLR4 and TLR3 signaling during the innate immune response. Caspase-11, also termed the non-canonical inflammasome, is activated by TLR3/TLR4-TRIF signaling and directly binds cytosolic lipopolysaccharide (LPS), a major structural element of Gram-negative bacterial cell walls. Activation of caspase-11 by LPS is known to cause the activation of other caspase proteins, leading to septic shock, pyroptosis, and often organismal death. [1]

Contents

History

LPS is a known activator of innate immune responses. Extracellular LPS binds specifically to the cell surface receptor TLR4. LPS binding to TLR4 subsequently causes initiation of the MyD88 and TRIF signaling pathways, leading to expression of pro-inflammatory molecules and cytokines. These inflammatory mediators cause host toxic shock and sepsis as a result of an overactive immune response to LPS. [2] Until recently, TLR4 was considered the sole receptor for LPS.

However, in 2013 it was shown that TLR4 knockout mice treated with the TLR3 ligand poly I:C still die of toxic shock induced by LPS treatment. Conversely, it was also found that poly I:C treated TLR4 and caspase-11 double knockout mice do not develop toxic shock in response to LPS. These results suggest that TLR4 is not the sole LPS receptor but that caspase-11 also responds to the presence of LPS. Caspase-11 was subsequently shown to be a cytosolic protein that responds solely to intracellular, cytosolic LPS. [3]

Though caspase-11 was thought to be activated only by TLR4, these experiments showed that it was in fact activated by TRIF signaling, mediated by both TLR4 and TLR3 stimulation. Caspase-11 can therefore mediate host LPS sensing even in the absence of TLR4, provided an alternative TRIF-dependent signal (e.g., by TLR3) is provided.

Mechanism

TRIF activation is necessary for the upregulation of pro-caspase-11 (an inactive precursor to active caspase-11) expression and caspase-11-mediated pyroptosis. [4] Once expressed, caspase-11 is only able to bind cytosolic LPS and cannot respond to extracellular LPS. Caspase-11 will only recognize the hexa- and penta-acylated forms of LPS. [3] LPS enters the cytosol through intracellular infection of vacuolar Gram-negative bacteria. These bacteria activate IFN-induced guanylate binding proteins, which are thought to mediate caspase-11 activation by promoting vacuolar lysis and release of bacteria and the LPS they produce into the cytoplasm. [5] [6]

Surprisingly, it has recently been shown that LPS activates caspase-11 not through a receptor/scaffold mediator, but through direct LPS binding to the caspase-11 CARD domain. [1] This mechanism contrasts to that of the canonical inflammasome, in which a bacterial ligand activates caspase-1 through an upstream sensor protein, and this is the reason why caspase-11 is often referred to as the non-canonical inflammasome. Caspase-11 activation by direct binding to LPS represents a novel and unprecedented mechanism for caspase activation. [1]

Caspase-11 activation results in pyroptosis, a form of lytic cell death that releases inflammatory molecules such as ATP, HMGB1 and IL-1α from the cytosol. Inflammatory cytokines such as IL-1β and IL-18 are also often produced. Production of IL-1β downstream of caspase-11 requires another canonical inflammasome, called the NLRP3 inflammasome, that activates caspase-1. [7] The mechanism linking caspase-11 to NLRP3 is not currently known.

Pyroptosis has been proposed to provide immune defense by exposing cytosolic bacteria infecting the pyroptotic cell to extracellular immune defenses, including other immune cells such as neutrophils. While caspase-11-mediated pyroptosis provides defense against pathogens, it has also been shown to cause damage to the host as well. [4]

The CARD domain of caspase-11 has been shown to associate with AIP-1 and cofilin to facilitate actin depolymerization. [8] In addition, association with the actin cytoskeleton surrounding the phagosome contributes to lysosome acidification. [9]

Chemical reaction

Caspase-11 (EC 3.4.22.64, CASP-11) is an protease enzyme that has a preferred cleavage sequence of (Ile/Leu/Val/Phe)-Gly-His-Asp, with a strict requirement for Asp at the P1 position. [10]

Medical relevance

Caspase-11 appears to provide immune defense against bacteria that enter or access the host cell cytosol. Caspase-11 has been shown to be activated by Burkholderia pseudomallei , Gram-negative bacteria found in the soil of southeast Asia that cause severe melioidosis. [3] Caspase-11 has been shown in vitro to be activated by Shigella flexneri infection, while a guinea pig model of Shigella infection has been shown to activate the human homolog of caspase-11, caspase-4. [3] For bacteria that do not typically access the host cytosol, caspase-11 is activated with delayed kinetics if Gram-negative bacteria aberrantly escape the vacuole and enter into the cytoplasm. [11]

Caspase-11 has been shown to contribute to lethality in mouse models of sepsis. [12] Toxic shock and sepsis may occur if too many host cells undergo pyroptosis, owing to either overstimulation of the immune system by the released cytoplasmic contents or to host cell depletion. [7] The mechanism by which pyroptosis contributes to septic shock and death is not well understood, although HMGB1 release is thought to play a role. [7]

Related Research Articles

<span class="mw-page-title-main">Caspase</span> Family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

<span class="mw-page-title-main">Lipopolysaccharide</span> Class of molecules found in the outer membrane of Gram-negative bacteria

Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by covalent bonds, and are found in the bacterial capsule, the outermost membrane of cell envelope of Gram-negative bacteria, such as E. coli and Salmonella. Today, the term endotoxin is often used synonymously with LPS, although there are a few endotoxins that are not related to LPS, such as the so-called delta endotoxin proteins produced by Bacillus thuringiensis.

<span class="mw-page-title-main">Toll-like receptor</span> Pain receptors and inflammation

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Humans lack genes for TLR11, TLR12 and TLR13 and mice lack a functional gene for TLR10. The receptors TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located on the cell membrane, whereas TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicles.

Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed mainly by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils, as well as by epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.

<span class="mw-page-title-main">Interleukin 1 beta</span> Mammalian protein found in Homo sapiens

Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the IL1B gene. There are two genes for interleukin-1 (IL-1): IL-1 alpha and IL-1 beta. IL-1β precursor is cleaved by cytosolic caspase 1 to form mature IL-1β.

<span class="mw-page-title-main">Caspase 1</span> Protein-coding gene in the species Homo sapiens

Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis inducer Gasdermin D, into active mature peptides. It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.

Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

<span class="mw-page-title-main">Toll-like receptor 4</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an intracellular signaling pathway NF-κB and inflammatory cytokine production which is responsible for activating the innate immune system.

<span class="mw-page-title-main">AIM2</span> Protein-coding gene in the species Homo sapiens

Interferon-inducible protein AIM2 also known as absent in melanoma 2 or simply AIM2 is a protein that in humans is encoded by the AIM2 gene.

<span class="mw-page-title-main">Inflammasome</span> Cytosolic multiprotein complex that mediates the activation of Caspase 1

Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as cleavage of gasdermin D. The N-terminal fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, and is responsible for secretion of the mature cytokines, presumably through the formation of pores in the plasma membrane. Additionally, inflammasomes can be incorporated into larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.

<span class="mw-page-title-main">Pyrin domain</span>

A pyrin domain is a protein domain and a subclass of protein motif known as the death fold, the 4th and most recently discovered member of the death domain superfamily (DDF). It was originally discovered in the pyrin protein, or marenostrin, encoded by MEFV. The mutation of the MEFV gene is the cause of the disease known as Familial Mediterranean Fever. The domain is encoded in 23 human proteins and at least 31 mouse genes.

<span class="mw-page-title-main">NLRP11</span> Protein-coding gene in the species Homo sapiens

NOD-like receptor family pyrin domain containing 11 is a protein that in humans is encoded by the NLRP11 gene located on the long arm of human chromosome 19q13.42. NLRP11 belongs to the NALP subfamily, part of a large subfamily of CATERPILLER. It is also known as NALP11, PYPAF6, NOD17, PAN10, and CLR19.6

<span class="mw-page-title-main">Stimulator of interferon genes</span> Protein-coding gene in the species Homo sapiens

Stimulator of interferon genes (STING), also known as transmembrane protein 173 (TMEM173) and MPYS/MITA/ERIS is a protein that in humans is encoded by the STING1 gene.

Immunogenic cell death is any type of cell death eliciting an immune response. Both accidental cell death and regulated cell death can result in immune response. Immunogenic cell death contrasts to forms of cell death that do not elicit any response or even mediate immune tolerance.

The interleukin-1 receptor (IL-1R) associated kinase (IRAK) family plays a crucial role in the protective response to pathogens introduced into the human body by inducing acute inflammation followed by additional adaptive immune responses. IRAKs are essential components of the Interleukin-1 receptor signaling pathway and some Toll-like receptor signaling pathways. Toll-like receptors (TLRs) detect microorganisms by recognizing specific pathogen-associated molecular patterns (PAMPs) and IL-1R family members respond the interleukin-1 (IL-1) family cytokines. These receptors initiate an intracellular signaling cascade through adaptor proteins, primarily, MyD88. This is followed by the activation of IRAKs. TLRs and IL-1R members have a highly conserved amino acid sequence in their cytoplasmic domain called the Toll/Interleukin-1 (TIR) domain. The elicitation of different TLRs/IL-1Rs results in similar signaling cascades due to their homologous TIR motif leading to the activation of mitogen-activated protein kinases (MAPKs) and the IκB kinase (IKK) complex, which initiates a nuclear factor-κB (NF-κB) and AP-1-dependent transcriptional response of pro-inflammatory genes. Understanding the key players and their roles in the TLR/IL-1R pathway is important because the presence of mutations causing the abnormal regulation of Toll/IL-1R signaling leading to a variety of acute inflammatory and autoimmune diseases.

<span class="mw-page-title-main">GSDMD</span> Protein found in humans

Gasdermin D (GSDMD) is a protein that in humans is encoded by the GSDMD gene on chromosome 8. It belongs to the gasdermin family which is conserved among vertebrates and comprises six members in humans, GSDMA, GSDMB, GSDMC, GSDMD, GSDME (DFNA5) and DFNB59 (Pejvakin). Members of the gasdermin family are expressed in a variety of cell types including epithelial cells and immune cells. GSDMA, GSDMB, GSDMC, GSDMD and GSDME have been suggested to act as tumour suppressors.

<span class="mw-page-title-main">Thirumala-Devi Kanneganti</span> Indian immunologist

Thirumala-Devi Kanneganti is an immunologist and is the Rose Marie Thomas Endowed Chair, Vice Chair of the Department of Immunology, and Member at St. Jude Children's Research Hospital. She is also Director of the Center of Excellence in Innate Immunity and Inflammation at St. Jude Children's Research Hospital. Her research interests include investigating fundamental mechanisms of innate immunity, including inflammasomes and inflammatory cell death, PANoptosis, in infectious and inflammatory disease and cancer.

<span class="mw-page-title-main">Vishva Dixit</span> Kenyan molecular biologist

Vishva Mitra Dixit is a physician of Indian origin who is the current Vice President of Discovery Research at Genentech.

PANoptosis is an inflammatory cell death pathway. Genetic, molecular, and biochemical studies identified extensive crosstalk among the molecular components across cell death pathways in response to a variety of pathogens and innate immune triggers, leading to the conceptualization of PANoptosis. PANoptosis is defined as a unique innate immune inflammatory cell death pathway driven by caspases and RIPKs and regulated by multi protein PANoptosome complexes. PANoptosis is implicated in driving innate immune responses and inflammation in disease. PANoptosome formation and PANoptosis occur during pathogenic infections, including bacterial, viral, and fungal infections, as well as during inflammatory diseases and can be beneficial in the context of cancer.

Jonathan C. Kagan is an American immunologist and the Marian R. Neutra, Ph.D. Professor of Pediatrics at Harvard Medical School. He is also the director of Basic Research and Shwachman Chair in Gastroenterology at Boston Children's Hospital. Kagan is a world leader in defining the molecular basis of innate immunity and inflammation.

References

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  2. ↑ Murphy K (2012). Janeway's Immunobiology. New York: Garland Science. ISBN   9780815342434.
  3. 1 2 3 4 Hagar JA, Miao EA (February 2014). "Detection of cytosolic bacteria by inflammatory caspases". Current Opinion in Microbiology. 17: 61–6. doi:10.1016/j.mib.2013.11.008. PMC   3942666 . PMID   24581694.
  4. 1 2 Broz P, Monack DM (February 2013). "Noncanonical inflammasomes: caspase-11 activation and effector mechanisms". PLOS Pathogens. 9 (2): e1003144. doi: 10.1371/journal.ppat.1003144 . PMC   3585133 . PMID   23468620.
  5. ↑ Pilla DM, Hagar JA, Haldar AK, Mason AK, Degrandi D, Pfeffer K, Ernst RK, Yamamoto M, Miao EA, Coers J (April 2014). "Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS". Proceedings of the National Academy of Sciences of the United States of America. 111 (16): 6046–51. Bibcode:2014PNAS..111.6046P. doi: 10.1073/pnas.1321700111 . PMC   4000848 . PMID   24715728.
  6. ↑ Meunier E, Dick MS, Dreier RF, Schürmann N, Kenzelmann Broz D, Warming S, Roose-Girma M, Bumann D, Kayagaki N, Takeda K, Yamamoto M, Broz P (May 2014). "Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases". Nature. 509 (7500): 366–70. Bibcode:2014Natur.509..366M. doi:10.1038/nature13157. PMID   24739961. S2CID   4454031.
  7. 1 2 3 Aachoui Y, Sagulenko V, Miao EA, Stacey KJ (June 2013). "Inflammasome-mediated pyroptotic and apoptotic cell death, and defense against infection". Current Opinion in Microbiology. 16 (3): 319–26. doi:10.1016/j.mib.2013.04.004. PMC   3742712 . PMID   23707339.
  8. ↑ Li J, Brieher WM, Scimone ML, Kang SJ, Zhu H, Yin H, von Andrian UH, Mitchison T, Yuan J (March 2007). "Caspase-11 regulates cell migration by promoting Aip1-Cofilin-mediated actin depolymerization". Nature Cell Biology. 9 (3): 276–86. doi:10.1038/ncb1541. PMID   17293856. S2CID   22073561.
  9. ↑ Monteith AJ, Vincent HA, Kang S, Li P, Claiborne TM, Rajfur Z, Jacobson K, Moorman NJ, Vilen BJ (July 2018). "mTORC2 Activity Disrupts Lysosome Acidification in Systemic Lupus Erythematosus by Impairing Caspase-1 Cleavage of Rab39a". Journal of Immunology. 201 (2): 371–382. doi:10.4049/jimmunol.1701712. PMC   6039264 . PMID   29866702.
  10. ↑ Kang SJ, Wang S, Hara H, Peterson EP, Namura S, Amin-Hanjani S, Huang Z, Srinivasan A, Tomaselli KJ, Thornberry NA, Moskowitz MA, Yuan J (May 2000). "Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions". The Journal of Cell Biology. 149 (3): 613–22. doi:10.1083/jcb.149.3.613. PMC   2174843 . PMID   10791975.
  11. ↑ Casson CN, Shin S (December 2013). "Inflammasome-mediated cell death in response to bacterial pathogens that access the host cell cytosol: lessons from legionella pneumophila". Frontiers in Cellular and Infection Microbiology. 3: 111. doi: 10.3389/fcimb.2013.00111 . PMC   3873505 . PMID   24409420.
  12. ↑ Jiménez Fernández D, Lamkanfi M (March 2015). "Inflammatory caspases: key regulators of inflammation and cell death". Biological Chemistry. 396 (3): 193–203. doi: 10.1515/hsz-2014-0253 . hdl: 1854/LU-5928516 . PMID   25389992.
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