Caspases in Cell Death, Inflammation, and Pyroptosis

Kesavardhana, Sannula; Malireddi, R.K. Subbarao; Kanneganti, Thirumala‐Devi

doi:10.1146/annurev-immunol-073119-095439

Cited by 587 publications

(470 citation statements)

References 207 publications

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“…Caspase-1 is activated via the inflammatory initiation factor NLRP3 that drives GSDMD pore formation on the membrane and ultimately results in programmed execution of cell death 33 . Measurement of pyroptosis-representative proteins by western blotting revealed significantly higher levels of NLRP3, caspase-1, Pro-IL-1β, IL-1β, and GSDMD in MCD keratocytes than in normal keratocytes (Fig.…”

Section: Resultsmentioning

confidence: 99%

Impairment of the autophagy-lysosomal pathway and activation of pyroptosis in macular corneal dystrophy

Zheng

Zhao

et al. 2020

Cell Death Discov.

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Macular corneal dystrophy (MCD) is ascribed to mutations in the carbohydrate sulfotransferase (CHST6) gene affecting keratan sulfate (KS) hydrophilicity and causing non-sulfated KS to precipitate in keratocytes and the corneal stroma. We investigated roles for inflammatory responses in MCD pathogenesis by examining the lysosomal-autophagy pathway and activation of pyroptosis in MCD keratocytes. Normal and lesioned keratocytes were obtained from MCD patients undergoing corneal transplantation. The keratocytes were subjected to gene sequencing, RT-PCR, western blotting, transmission electron microscopy, histological staining, induction and inhibition assays of autophagy and pyroptosis, CCK-8 and LysoTracker Green DND-26 labeling, and flow cytometry. A novel homozygous MCD mutation was identified in a family from Northeast China; the mutation was distinguished by cytoplasmic vacuolation, cell membrane disruption, electron dense deposits, and deposition of a band of Periodic acid-Schiff and Alcian blue-positive material in the keratocytes and stroma layer. KS protein levels were decreased, expression of p62 and LC3-II proteins was enhanced, cathepsin D expression was declined and the LysoTracker Green DND-26 signal was dramatically reduced in MCD keratocytes. Bafilomycin-A1 treatment significantly increased caspase-1 and Pro-IL-1β expression in normal and MCD keratocytes. Nod-like receptors pyrins-3 (NLRP3), caspase-1, Pro-IL-1β, and IL-1β levels were pronouncedly elevated in cells exposed to H2O2. Ac-YVAD-CMK treatment reversed this expression in normal and MCD keratocytes. Suppression of the autophagic degradation of non-sulfated KS by impaired autophagic flux in MCD keratocytes triggers pyroptosis. Amelioration of impaired autophagy and restraint of pyroptosis may, therefore, have therapeutic efficacy in the treatment of MCD.

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Section: Resultsmentioning

confidence: 99%

Impairment of the autophagy-lysosomal pathway and activation of pyroptosis in macular corneal dystrophy

Zheng

Zhao

et al. 2020

Cell Death Discov.

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“…Identification of a RHIM domain in ZBP1 facilitated its characterization in cell death and inflammation (3,4,11). The RHIM-containing proteins regulate inflammatory signaling, apoptosis, and inflammatory cell death (1). Initial reports on ZBP1 suggested it plays a role in virus-induced necroptosis via its RHIM-mediated interaction with RIPK3 (3,4).…”

Section: Discussionmentioning

confidence: 99%

“…Activation of inflammation and cell death are interconnected cellular events which regulate host defense and immune responses. RIP homotypic interaction motif (RHIM)family proteins play a major role in orchestrating inflammation and cell death to profoundly shape immune responses and host defense (1,2). Z-DNA-binding protein 1 (ZBP1) is one such RHIM protein that interacts with the RHIM proteins receptor-interacting protein kinase 3 (RIPK3) and receptor-interacting protein kinase 1 (RIPK1) by forming homotypic interactions (3).…”

Section: Introductionmentioning

confidence: 99%

Zα2 domain of ZBP1 is a molecular switch regulating Influenza-induced PANoptosis and perinatal lethality during development

Kesavardhana

Malireddi

Burton

et al. 2020

Preprint

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ABSTRACTZ-DNA-binding protein 1 (ZBP1) is an innate nucleic acid sensor which regulates host defense responses and development. ZBP1 activation triggers inflammation and pyroptosis, necroptosis, and apoptosis (PANoptosis) by activating RIPK3, caspase-8, and the NLRP3 inflammasome. ZBP1 is unique among innate sensors because of its N-terminal Zα1 and Zα2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zα domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we have generated Zbp1ΔZα2/ΔZα2 mice that lack the Zα2 domain of ZBP1 and demonstrate that this domain is critical for influenza A virus (IAV)-induced PANoptosis and perinatal lethality in RIPK1-RHIM mutated (Ripk1RHIM/RHIM) mice. Deletion of the Zα2 domain in ZBP1 abolished IAV-induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zα2 domain of ZBP1 was sufficient to rescue Ripk1RHIM/RHIM mice from the perinatal lethality which is caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zα2 domain of ZBP1 in physiological functions and establish a link between sensing of Z-RNAs via the Zα2 domain and the promotion of influenza-induced PANoptosis and perinatal lethality.

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“…induces pyroptotic cell death downstream of caspase‐11 activation. Active caspase‐11 and caspase‐1 cleaves GSDMD to release N‐terminal fragment of GSDMD, which then assembles pores in the cell membrane to promote pyroptotic cell death 105 . It not yet known whether GSDMD is required during Leishmania spp.…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

Reconciling protective and pathogenic roles of the NLRP3 inflammasome in leishmaniasis

Harrington

Gurung

2020

Immunological Reviews

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Leishmaniasis is a global health problem that affects more than 2 billion people worldwide. Recent advances in research have demonstrated critical roles for cytoplasmic sensors and inflammasomes during Leishmania spp. infection and pathogenesis. Specifically, several studies have focused on the role of nod‐like receptor family, pyrin domain‐containing protein 3 (NLRP3) inflammasome and inflammasome‐associated cytokines IL‐1β and IL‐18 in leishmaniasis. Despite these studies, our understanding of the priming and activation events that lead to NLRP3 inflammasome activation during Leishmania spp. infection is limited. Furthermore, whether NLRP3 plays a protective or pathogenic role during Leishmania spp. infection is far from resolved, with some studies showing a protective role and others showing a pathogenic role. In this review, we performed a critical review of the literature to provide a current update on priming and activating signals required for NLRP3 inflammasome activation during Leishmania spp. infection. Finally, we provide a thorough review of the literature to reconcile differences in the observed protective vs pathogenic roles of the NLRP3 inflammasome during Leishmania spp. infection.

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Caspases in Cell Death, Inflammation, and Pyroptosis

Cited by 587 publications

References 207 publications

Impairment of the autophagy-lysosomal pathway and activation of pyroptosis in macular corneal dystrophy

Impairment of the autophagy-lysosomal pathway and activation of pyroptosis in macular corneal dystrophy

Zα2 domain of ZBP1 is a molecular switch regulating Influenza-induced PANoptosis and perinatal lethality during development

Reconciling protective and pathogenic roles of the NLRP3 inflammasome in leishmaniasis

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