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  1. Article ; Online: Cell organelles are retained inside pyroptotic corpses during inflammatory cell death.

    Hempel, Anne / D'Osualdo, Andrea / Snipas, Scott J / Salvesen, Guy S

    Bioscience reports

    2023  Volume 43, Issue 10

    Abstract: Many proinflammatory proteins are released via the necrotic form of cell death known as pyroptosis. Sometimes known as gasdermin D (GSDMD) dependent cell death, pyroptosis results from the formation of pores in the plasma membrane leading to eventual ... ...

    Abstract Many proinflammatory proteins are released via the necrotic form of cell death known as pyroptosis. Sometimes known as gasdermin D (GSDMD) dependent cell death, pyroptosis results from the formation of pores in the plasma membrane leading to eventual cell lysis. Seeking to understand the magnitude of this cell lysis we measured the size of proteins released during pyroptosis. We demonstrate that there is no restriction on the size of soluble proteins released during pyroptosis even at early timepoints. However, even though large molecules can exit the dying cell, organelles are retained within it. This observation indicates that complete cell rupture may not be a consequence of pyroptosis, and that plasma membrane architecture is retained.
    MeSH term(s) Intracellular Signaling Peptides and Proteins ; Inflammasomes/metabolism ; Pyroptosis ; Apoptosis Regulatory Proteins/metabolism ; Organelles/metabolism
    Chemical Substances Intracellular Signaling Peptides and Proteins ; Inflammasomes ; Apoptosis Regulatory Proteins
    Language English
    Publishing date 2023-10-05
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 764946-0
    ISSN 1573-4935 ; 0144-8463
    ISSN (online) 1573-4935
    ISSN 0144-8463
    DOI 10.1042/BSR20231265
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Caspase mechanisms in the regulation of inflammation.

    Bibo-Verdugo, Betsaida / Salvesen, Guy S

    Molecular aspects of medicine

    2022  Volume 88, Page(s) 101085

    Abstract: Regulated cell death is defined as genetically encoded pathways that lead towards the demise of cells. In mammals, cell demise can be either inflammatory or non-inflammatory, depending on whether the mechanism of death results in cell rupture or not. ... ...

    Abstract Regulated cell death is defined as genetically encoded pathways that lead towards the demise of cells. In mammals, cell demise can be either inflammatory or non-inflammatory, depending on whether the mechanism of death results in cell rupture or not. Inflammatory cell death can lead towards acute and chronic disease. Therefore, it becomes important to distinguish the mechanisms that result in these different inflammatory cell death outcomes. Apoptosis is a non-inflammatory form of cell death where cells resist rupture. In contrast, pyroptosis and necroptosis are inflammatory forms of cell death principally because of release of pro-inflammatory mediators from cells undergoing lysis. This review focusses on the mechanisms of these different cell death outcomes with specific emphasis on the caspase family of proteolytic enzymes.
    Language English
    Publishing date 2022-03-02
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 197640-0
    ISSN 1872-9452 ; 0098-2997
    ISSN (online) 1872-9452
    ISSN 0098-2997
    DOI 10.1016/j.mam.2022.101085
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Differential specificity of SARS-CoV-2 main protease variants on peptide versus protein-based substrates.

    Rocho, Fernanda R / Snipas, Scott J / Shamim, Anwar / Rut, Wioletta / Drag, Marcin / Montanari, Carlos A / Salvesen, Guy S

    The FEBS journal

    2023  Volume 291, Issue 1, Page(s) 61–69

    Abstract: The SARS-CoV-2 main protease ( ... ...

    Abstract The SARS-CoV-2 main protease (M
    MeSH term(s) Humans ; SARS-CoV-2/genetics ; COVID-19/genetics ; Viral Nonstructural Proteins/genetics ; Peptides/genetics ; Coronavirus 3C Proteases/genetics ; Protease Inhibitors/chemistry ; Antiviral Agents/pharmacology ; Peptide Hydrolases
    Chemical Substances 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Viral Nonstructural Proteins ; Peptides ; Coronavirus 3C Proteases (EC 3.4.22.28) ; Protease Inhibitors ; Antiviral Agents ; Peptide Hydrolases (EC 3.4.-)
    Language English
    Publishing date 2023-11-03
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/febs.16970
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Selective inhibition of matrix metalloproteinase 10 (MMP10) with a single-domain antibody.

    Razai, Amir S / Eckelman, Brendan P / Salvesen, Guy S

    The Journal of biological chemistry

    2020  Volume 295, Issue 8, Page(s) 2464–2472

    Abstract: Since their discovery, the matrix metalloproteinase (MMP) family proteases have been considered as therapeutic targets in numerous diseases and disorders. Unfortunately, clinical trials with MMP inhibitors have failed to yield any clinical benefits of ... ...

    Abstract Since their discovery, the matrix metalloproteinase (MMP) family proteases have been considered as therapeutic targets in numerous diseases and disorders. Unfortunately, clinical trials with MMP inhibitors have failed to yield any clinical benefits of these inhibitors. These failures were largely due to a lack of MMP-selective agents; accordingly, it has become important to identify a platform with which high selectivity can be achieved. To this end, we propose using MMP-targeting antibodies that can achieve high specificity in interactions with their targets. Using a scaffold of single-domain antibodies, here we raised a panel of MMP10-selective antibodies through immunization of llamas, a member of the camelid family, whose members generate conventional heavy/light-chain antibodies and also smaller antibodies lacking light-chain and CH1 domains. We report the generation of a highly selective and tightly binding MMP10 inhibitor (
    MeSH term(s) Animals ; Camelids, New World ; Humans ; Immunization ; Kinetics ; Matrix Metalloproteinase 10/metabolism ; Matrix Metalloproteinase Inhibitors/pharmacology ; Peptide Library ; Recombinant Proteins/metabolism ; Saccharomyces cerevisiae/metabolism ; Single-Domain Antibodies/pharmacology ; Substrate Specificity/drug effects ; alpha 1-Antitrypsin/metabolism
    Chemical Substances Matrix Metalloproteinase Inhibitors ; Peptide Library ; Recombinant Proteins ; Single-Domain Antibodies ; alpha 1-Antitrypsin ; Matrix Metalloproteinase 10 (EC 3.4.24.22)
    Language English
    Publishing date 2020-01-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.RA119.011712
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Gain of function of a metalloproteinase associated with multiple myeloma, bicuspid aortic valve, and Von Hippel-Lindau syndrome.

    Snipas, Scott J / Jappelli, Roberto / Torkamani, Ali / Paternostro, Giovanni / Salvesen, Guy S

    The Biochemical journal

    2022  Volume 479, Issue 14, Page(s) 1533–1542

    Abstract: A patient diagnosed with multiple myeloma, bicuspid aortic valve, and Von Hippel-Lindau syndrome underwent whole-exome sequencing seeking a unified genetic cause for these three pathologies. The patient possessed a single-point mutation of arginine to ... ...

    Abstract A patient diagnosed with multiple myeloma, bicuspid aortic valve, and Von Hippel-Lindau syndrome underwent whole-exome sequencing seeking a unified genetic cause for these three pathologies. The patient possessed a single-point mutation of arginine to cysteine (R24C) in the N-terminal region(pro-domain) of matrix metalloproteinase 9 (MMP-9). The pro-domain interacts with the catalytic site of this enzyme rendering it inactive. MMP-9 has previously been associated with all three pathologies suffered by the patient. We hypothesized that the observed mutation in the pro-domain would influence the activity of this enzyme. We expressed recombinant versions of MMP-9 and an investigation of their biochemical properties revealed that MMP-9 R24C is a constitutively active zymogen. To our knowledge, this is the first example of a mutation that discloses catalytic activity in the pro-form in any of the 24 human MMPs.
    MeSH term(s) Bicuspid Aortic Valve Disease ; Gain of Function Mutation ; Humans ; Matrix Metalloproteinase 9/genetics ; Multiple Myeloma/complications ; Multiple Myeloma/genetics ; von Hippel-Lindau Disease/complications ; von Hippel-Lindau Disease/genetics
    Chemical Substances Matrix Metalloproteinase 9 (EC 3.4.24.35)
    Language English
    Publishing date 2022-07-05
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BCJ20220166
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in a mouse model of retinal vein occlusion.

    Avrutsky, Maria I / Chen, Claire W / Lawson, Jacqueline M / Snipas, Scott J / Salvesen, Guy S / Troy, Carol M

    Frontiers in neuroscience

    2023  Volume 17, Page(s) 1209527

    Abstract: Purpose: Retinal vein occlusion (RVO) is a sight-threatening condition typically treated with intravitreal injection of vascular endothelial growth factor (VEGF) antagonists. Treatment response to anti-VEGF therapies is highly variable, with poor visual ...

    Abstract Purpose: Retinal vein occlusion (RVO) is a sight-threatening condition typically treated with intravitreal injection of vascular endothelial growth factor (VEGF) antagonists. Treatment response to anti-VEGF therapies is highly variable, with poor visual outcomes and treatment response in patients with significant retinal nonperfusion following RVO. Recently, caspase-9 has been identified as a potent regulator of edema, gliosis, and neuronal dysfunction during acute retinal hypoxia. The purpose of this study was to compare the therapeutic effect of caspase-9 inhibition against VEGF-neutralization in an established mouse model of RVO.
    Methods: Adult male C57Bl/6 J mice were randomized to induction of RVO and treatment with either vehicle, intravitreal injection of anti-VEGF antibody, topical administration of a selective caspase-9 inhibitor (Pen1-XBir3), or a combination therapy. Animals were followed on days 1, 2, and 8 after RVO with fundus retinal imaging, and with optical coherence tomography (OCT) to capture retinal swelling, capillary nonperfusion (measured by disorganization of retinal inner layers, DRIL), hyperreflective foci (HRF), and retinal atrophy. Focal electroretinography (ERG) measurements were performed on day 7. Histology was performed on retinal sections from day 8.
    Results: Both VEGF neutralization and caspase-9 inhibition showed significant retinal protection from RVO compared to vehicle treatment arm. Retinal reperfusion of occluded veins was accelerated in eyes receiving caspase-9 inhibitor, but not significantly different from vehicle in the anti-VEGF group. Retinal edema was suppressed in all treatment groups, with approximately 2-fold greater edema reduction with caspase-9 inhibition compared to VEGF neutralization. HRF were reduced similarly across all treatment groups compared to vehicle. Retinal detachment was reduced only in eyes treated with caspase-9 inhibitor monotherapy. Caspase-9 inhibition reduced retinal atrophy and preserved ERG response; VEGF neutralization did not prevent neurodegeneration following RVO.
    Conclusion: Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in the mouse laser-induced model of RVO.
    Language English
    Publishing date 2023-06-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2411902-7
    ISSN 1662-453X ; 1662-4548
    ISSN (online) 1662-453X
    ISSN 1662-4548
    DOI 10.3389/fnins.2023.1209527
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: The Paracaspase MALT1.

    Hachmann, Janna / Salvesen, Guy S

    Biochimie

    2016  Volume 122, Page(s) 324–338

    Abstract: The human paracaspase MALT1 is a caspase homolog that plays a central role in NF-κB signaling. Over the past few years it has become clear that this is due to a combination of its scaffolding and proteolytic function. Knockout mice and mice expressing a ... ...

    Abstract The human paracaspase MALT1 is a caspase homolog that plays a central role in NF-κB signaling. Over the past few years it has become clear that this is due to a combination of its scaffolding and proteolytic function. Knockout mice and mice expressing a catalytically dead variant of the protease have provided valuable information. This review aims to provide an overview of recent developments regarding the enzymatic mechanism and specificity of MALT1, its substrates discovered to date, different mouse models, as well as the role of MALT1 in NF-κB signaling downstream of a variety of different receptors.
    MeSH term(s) Animals ; Caspases/genetics ; Caspases/metabolism ; Encephalomyelitis, Autoimmune, Experimental/genetics ; Genetic Predisposition to Disease/genetics ; Humans ; Lymphoma, B-Cell, Marginal Zone/genetics ; Mice, Knockout ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein ; NF-kappa B/metabolism ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Proteolysis ; Signal Transduction
    Chemical Substances NF-kappa B ; Neoplasm Proteins ; Caspases (EC 3.4.22.-) ; MALT1 protein, human (EC 3.4.22.-) ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein (EC 3.4.22.-)
    Language English
    Publishing date 2016-03
    Publishing country France
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 120345-9
    ISSN 1638-6183 ; 0300-9084
    ISSN (online) 1638-6183
    ISSN 0300-9084
    DOI 10.1016/j.biochi.2015.09.018
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Evaluation of the effects of phosphorylation of synthetic peptide substrates on their cleavage by caspase-3 and -7.

    Maluch, Izabela / Grzymska, Justyna / Snipas, Scott J / Salvesen, Guy S / Drag, Marcin

    The Biochemical journal

    2021  Volume 478, Issue 12, Page(s) 2233–2245

    Abstract: Caspases are a family of enzymes that play roles in cell death and inflammation. It has been suggested that in the execution phase of the apoptotic pathway, caspase-3, -6 and -7 are involved. The substrate specificities of two proteases (caspases 3 and 7) ...

    Abstract Caspases are a family of enzymes that play roles in cell death and inflammation. It has been suggested that in the execution phase of the apoptotic pathway, caspase-3, -6 and -7 are involved. The substrate specificities of two proteases (caspases 3 and 7) are highly similar, which complicates the design of compounds that selectively interact with a single enzyme exclusively. The recognition of residues other than Asp in the P1 position of the substrate by caspase-3/-7 has been reported, promoting interest in the effects of phosphorylation of amino acids in the direct vicinity of the scissile bond. To evaluate conflicting reports on this subject, we synthesized a series of known caspase-3 and -7 substrates and phosphorylated analogs, performed enzyme kinetic assays and mapped the peptide cleavage sites using internally quenched fluorescent peptide substrates. Caspases 3 and 7 will tolerate pSer at the P1 position but only poorly at the P2' position. Our investigation demonstrates the importance of peptide length and composition in interpreting sequence/activity relationships. Based on the results, we conclude that the relationship between caspase-3/-7 and their substrates containing phosphorylated amino acids might depend on the steric conditions and not be directly connected with ionic interactions. Thus, the precise effect of phospho-amino acid residues located in the vicinity of the cleaved bond on the regulation of the substrate specificity of caspases remains difficult to predict. Our observations allow to predict that natural phosphorylated proteins may be cleaved by caspases, but only when extended substrate binding site interactions are satisfied.
    MeSH term(s) Adaptor Proteins, Signal Transducing/chemistry ; Binding Sites ; Caspase 3/genetics ; Caspase 3/metabolism ; Caspase 7/genetics ; Caspase 7/metabolism ; Humans ; Kinetics ; Models, Molecular ; Peptide Fragments/metabolism ; Phosphorylation ; Proteolysis ; Serine/chemistry ; Serine/metabolism ; Substrate Specificity ; Transcription Factors/chemistry ; Vimentin/chemistry
    Chemical Substances Adaptor Proteins, Signal Transducing ; Peptide Fragments ; Transcription Factors ; VIM protein, human ; Vimentin ; YAP1 protein, human ; Serine (452VLY9402) ; CASP3 protein, human (EC 3.4.22.-) ; CASP7 protein, human (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Caspase 7 (EC 3.4.22.-)
    Language English
    Publishing date 2021-06-07
    Publishing country England
    Document type Evaluation Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BCJ20210255
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: A primer on caspase mechanisms.

    Ramirez, Monica L Gonzalez / Salvesen, Guy S

    Seminars in cell & developmental biology

    2018  Volume 82, Page(s) 79–85

    Abstract: Caspases belong to a diverse clan of proteolytic enzymes known as clan CD with highly disparate functions in cell signaling. The caspase members of this clan are only found in animals, and most of them orchestrate the demise of cells by the highly ... ...

    Abstract Caspases belong to a diverse clan of proteolytic enzymes known as clan CD with highly disparate functions in cell signaling. The caspase members of this clan are only found in animals, and most of them orchestrate the demise of cells by the highly distinct regulated cell death phenotypes known as apoptosis and pyroptosis. This review looks at the mechanistic distinctions between the activity and activation mechanisms of mammalian caspases compared to other members of clan CD. We also compare and contrast the role of different caspase family members that program anti-inflammatory and pro-inflammatory cell death pathways.
    MeSH term(s) Caspases/metabolism ; Humans
    Chemical Substances Caspases (EC 3.4.22.-)
    Language English
    Publishing date 2018-01-12
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 1312473-0
    ISSN 1096-3634 ; 1084-9521
    ISSN (online) 1096-3634
    ISSN 1084-9521
    DOI 10.1016/j.semcdb.2018.01.002
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    Zs.A 2918: Show issues Location:
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  10. Article ; Online: Oxidation of caspase-8 by hypothiocyanous acid enables TNF-mediated necroptosis.

    Bozonet, Stephanie M / Magon, Nicholas J / Schwartfeger, Abigail J / Konigstorfer, Andreas / Heath, Sarah G / Vissers, Margreet C M / Morris, Vanessa K / Göbl, Christoph / Murphy, James M / Salvesen, Guy S / Hampton, Mark B

    The Journal of biological chemistry

    2023  Volume 299, Issue 6, Page(s) 104792

    Abstract: Necroptosis is a form of regulated cell death triggered by various host and pathogen-derived molecules during infection and inflammation. The essential step leading to necroptosis is phosphorylation of the mixed lineage kinase domain-like protein by ... ...

    Abstract Necroptosis is a form of regulated cell death triggered by various host and pathogen-derived molecules during infection and inflammation. The essential step leading to necroptosis is phosphorylation of the mixed lineage kinase domain-like protein by receptor-interacting protein kinase 3. Caspase-8 cleaves receptor-interacting protein kinases to block necroptosis, so synthetic caspase inhibitors are required to study this process in experimental models. However, it is unclear how caspase-8 activity is regulated in a physiological setting. The active site cysteine of caspases is sensitive to oxidative inactivation, so we hypothesized that oxidants generated at sites of inflammation can inhibit caspase-8 and promote necroptosis. Here, we discovered that hypothiocyanous acid (HOSCN), an oxidant generated in vivo by heme peroxidases including myeloperoxidase and lactoperoxidase, is a potent caspase-8 inhibitor. We found HOSCN was able to promote necroptosis in mouse fibroblasts treated with tumor necrosis factor. We also demonstrate purified caspase-8 was inactivated by low concentrations of HOSCN, with the predominant product being a disulfide-linked dimer between Cys360 and Cys409 of the large and small catalytic subunits. We show oxidation still occurred in the presence of reducing agents, and reduction of the dimer was slow, consistent with HOSCN being a powerful physiological caspase inhibitor. While the initial oxidation product is a dimer, further modification also occurred in cells treated with HOSCN, leading to higher molecular weight caspase-8 species. Taken together, these findings indicate major disruption of caspase-8 function and suggest a novel mechanism for the promotion of necroptosis at sites of inflammation.
    MeSH term(s) Animals ; Mice ; Caspase 8/chemistry ; Caspase 8/metabolism ; Inflammation/metabolism ; Necroptosis/drug effects ; Oxidants/metabolism ; Oxidants/pharmacology ; Oxidation-Reduction/drug effects ; Tumor Necrosis Factors/metabolism ; Fibroblasts/drug effects ; Fibroblasts/enzymology ; Fibroblasts/metabolism ; Peroxidase ; Lactoperoxidase ; Catalytic Domain
    Chemical Substances Caspase 8 (EC 3.4.22.-) ; hypothiocyanous acid ; Oxidants ; Tumor Necrosis Factors ; Peroxidase (EC 1.11.1.7) ; Lactoperoxidase (EC 1.11.1.-)
    Language English
    Publishing date 2023-05-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2023.104792
    Database MEDical Literature Analysis and Retrieval System OnLINE

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