Dimerization and auto-processing induce caspase-11 protease activation within the non-canonical inflammasome

Ross, Connie M.; Chan, Amy H; Pein, Jessica B. von; Boucher, Dave; Schroder, Kate

doi:10.26508/lsa.201800237

Cited by 60 publications

(77 citation statements)

References 39 publications

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“…Caspase-4, caspase-5, and caspase-11 directly interact with LPS (Shi et al, 2014), but physiological bacterial detection by these caspases occurs with the assistance of guanylate-binding proteins (Liu et al, 2018), whose functions in LPS sensing await full clarification. LPS interaction with two or more caspase-11 monomers triggers the dimerization of the caspase protease domains to induce basal protease activity (Ross et al, 2018). This leads to autoprocessing at the caspase-11 interdomain linker (residue D285), generating a p32/p10 species with full protease activity (Lee et al, 2018; Ross et al, 2018).…”

Section: Inflammasomes Govern the Maturation Of Il-1β Il-18 And Il-37mentioning

confidence: 99%

“…LPS interaction with two or more caspase-11 monomers triggers the dimerization of the caspase protease domains to induce basal protease activity (Ross et al, 2018). This leads to autoprocessing at the caspase-11 interdomain linker (residue D285), generating a p32/p10 species with full protease activity (Lee et al, 2018; Ross et al, 2018). Caspase-4/5/11 then cleave GSDMD to trigger GSDMD pores and initiate pyroptotic cell lysis (He et al, 2015; Kayagaki et al, 2015; Shi et al, 2015; Aglietti et al, 2016; Ding et al, 2016; Liu et al, 2016), or pyroptosis-associated expulsion of neutrophil extracellular traps (Chen et al, 2018).…”

Section: Inflammasomes Govern the Maturation Of Il-1β Il-18 And Il-37mentioning

confidence: 99%

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Inflammasome signaling and regulation of interleukin-1 family cytokines

Chan

Schroder

2019

Journal of Experimental Medicine

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266

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Specific IL-1 family cytokines are expressed by cells as cytosolic pro-forms that require cleavage for their activity and cellular release. IL-1β, IL-18, and IL-37 maturation and secretion is governed by inflammatory caspases within signaling platforms called inflammasomes. By inducing pyroptosis, inflammasomes can also drive the release of the alarmin IL-1α. Recent advances have transformed our mechanistic understanding of inflammasome signaling, cell death decisions, and cytokine activation and secretion. Here, we provide an updated view of inflammasome signaling; mechanisms underpinning IL-1α, IL-1β, IL-18, and IL-37 maturation and release; and the functions of these cytokines in protective and pathological inflammation.

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Section: Inflammasomes Govern the Maturation Of Il-1β Il-18 And Il-37mentioning

confidence: 99%

Section: Inflammasomes Govern the Maturation Of Il-1β Il-18 And Il-37mentioning

confidence: 99%

Inflammasome signaling and regulation of interleukin-1 family cytokines

Chan

Schroder

2019

Journal of Experimental Medicine

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266

208

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“…Replacing CARDs with the DmrB domain enables the smallmolecule (AP-20187)-induced dimerization, autoproteolysis, and activation of caspases (Oberst et al, 2010;Boucher et al, 2018;Ross et al, 2018;Ruhl et al, 2018). To confirm that IDL cleavage was required for proximity-induced pro-caspase-1 activation, we cloned DmrB-caspase-1 constructs with the IDL mutations described above ( Fig S2D).…”

Section: Human Pro-caspase-1 Interdomain Linker (Idl) Cleavage Is Reqmentioning

confidence: 99%

“…Autoproteolysis is similarly a key step in the activation of other caspases (Kang et al, 2008;Kallenberger et al, 2014). In particular, two recent studies have demonstrated that the related inflammatory caspase-11, which only forms an ASCindependent inflammasome (termed the "non-canonical" inflammasome) with often little detectable self-cleavage and no direct IL-1β processing (Hagar et al, 2013;Yang et al, 2015), also requires IDL autoproteolysis for activation (Lee et al, 2018;Ross et al, 2018). In this way, the ASC-independent caspase-1 canonical inflammasome is similar to the non-canonical caspase-11 inflammasome.…”

Section: Cleavage Of the Mouse Pro-caspase-1 Idl Is Critical For Pyromentioning

confidence: 99%

Caspase-1 interdomain linker cleavage is required for pyroptosis

et al. 2020

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Pathogen-related signals induce a number of cytosolic pattern-recognition receptors (PRRs) to form canonical inflammasomes, which activate pro-caspase-1 and trigger pyroptotic cell death. All well-studied inflammasome-forming PRRs oligomerize with the adapter protein ASC (apoptosis-associated speck-like protein containing a CARD) to generate a large structure in the cytosol, which induces the dimerization, autoproteolysis, and activation of the pro-caspase-1 zymogen. However, several PRRs can also directly interact with pro-caspase-1 without ASC, forming smaller “ASC-independent” inflammasomes. It is currently thought that little, if any, pro-caspase-1 autoproteolysis occurs during, and is not required for, ASC-independent inflammasome signaling. Here, we show that the related human PRRs NLRP1 and CARD8 exclusively form ASC-dependent and ASC-independent inflammasomes, respectively, identifying CARD8 as the first canonical inflammasome-forming PRR that does not form an ASC-containing signaling platform. Despite their different structures, we discovered that both the NLRP1 and CARD8 inflammasomes require pro-caspase-1 autoproteolysis between the small and large catalytic subunits to induce pyroptosis. Thus, pro-caspase-1 self-cleavage is a required regulatory step for pyroptosis induced by human canonical inflammasomes.

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“…Dimerization of caspase‐11 is sufficient for caspase‐11 to acquire basal proteolytic activity. However, full spectrum of caspase‐11 activities such as cleavage of gasdermin D, macrophage death, NLRP3 inflammasome activation, and IL‐1β release requires dimerization of caspase‐11 and auto‐cleavage 45 . Indeed, caspase‐11 harbors multiple candidate sites within CDL and IDL for auto‐cleavage, which could generate fragments of multiple sizes.…”

Section: Caspase‐11 Protease Activity and Substrate Specificitymentioning

confidence: 99%

Pyroptotic and non‐pyroptotic effector functions of caspase‐11

Khweek

Amer

2020

Immunological Reviews

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Innate immune cells, epithelial cells, and many other cell types are capable of detecting infection or tissue injury, thus mounting regulated immune response. Inflammasomes are highly sophisticated and effective orchestrators of innate immunity. These oligomerized multiprotein complexes are at the center of various innate immune pathways, including modulation of the cytoskeleton, production and maturation of cytokines, and control of bacterial growth and cell death. Inflammasome assembly often results in caspase‐1 activation, which is an inflammatory caspase that is involved in pyroptotic cell death and release of inflammatory cytokines in response to pathogen patterns and endogenous danger stimuli. However, the nature of stimuli and inflammasome components are diverse. Caspase‐1 activation mediated release of mature IL‐1β and IL‐18 in response to canonical stimuli initiated by NOD‐like receptor (NLR), and apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC). On the other hand, caspase‐11 delineates a non‐canonical inflammasome that promotes pyroptotic cell death and non‐pyroptotic functions in response to non‐canonical stimuli. Caspase‐11 in mice and its homologues in humans (caspase‐4/5) belong to caspase‐1 family of cysteine proteases, and play a role in inflammation. Knockout mice provided new genetic tools to study inflammatory caspases and revealed the role of caspase‐11 in mediating septic shock in response to lethal doses of lipopolysaccharide (LPS). Recognition of LPS mediates caspase‐11 activation, which promotes a myriad of downstream effects that include pyroptotic and non‐pyroptotic effector functions. Therefore, the physiological functions of caspase‐11 are much broader than its previously established roles in apoptosis and cytokine maturation. Inflammation induced by exogenous or endogenous agents can be detrimental and, if excessive, can result in organ and tissue damage. Consequently, the existence of sophisticated mechanisms that tightly regulate the specificity and sensitivity of inflammasome pathways provides a fine‐tuning balance between adequate immune response and minimal tissue damage. In this review, we summarize effector functions of caspase‐11.

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Dimerization and auto-processing induce caspase-11 protease activation within the non-canonical inflammasome

Abstract: This study provides a detailed molecular mechanism for caspase-11 activation within the non-canonical inflammasome, giving new insight into host defence against cytosolic bacterial infection.

Cited by 60 publications

References 39 publications

Inflammasome signaling and regulation of interleukin-1 family cytokines

Inflammasome signaling and regulation of interleukin-1 family cytokines

Caspase-1 interdomain linker cleavage is required for pyroptosis

Pyroptotic and non‐pyroptotic effector functions of caspase‐11

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