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Article ; Online: Unconventional protein secretion by gasdermin pores.

Broz, Petr

2023 Volume 69, Page(s) 101811

Abstract: Unconventional protein secretion (UPS) allows the release of specific leaderless proteins independently of the classical endoplasmic reticulum (ER)-Golgi secretory pathway. While it remains one of the least understood mechanisms in cell biology, UPS ... ...

Abstract	Unconventional protein secretion (UPS) allows the release of specific leaderless proteins independently of the classical endoplasmic reticulum (ER)-Golgi secretory pathway. While it remains one of the least understood mechanisms in cell biology, UPS plays an essential role in immunity as it controls the release of the IL-1 family of cytokines, which coordinate host defense and inflammatory responses. The unconventional secretion of IL-1β and IL-18, the two most prominent members of the IL-1 family, is initiated by inflammasome complexes - cytosolic signaling platforms that are assembled in response to infectious or noxious stimuli. Inflammasomes activate inflammatory caspases that proteolytically mature IL-1β/- 18, but also induce pyroptosis, a lytic form of cell death. Pyroptosis is caused by gasdermin-D (GSDMD), a member of the gasdermin protein family, which is activated by caspase cleavage and forms large β-barrel plasma membrane pores. This pore-forming activity is shared with other family members that are activated during infection or upon treatment with chemotherapy drugs. While the induction of cell death was assumed to be the main function of gasdermin pores, accumulating evidence suggests that they have also non-lytic functions, such as in the release of cytokines and alarmins, or in regulating ion fluxes. This has raised the possibility that gasdermin pores are one of the main mediators of UPS. Here, I summarize and discuss new insights into gasdermin activation and pore formation, how gasdermin pores achieve selective cargo release, and how gasdermin pore formation and ninjurin-1-driven plasma membrane rupture are executed and regulated.
MeSH term(s)	Humans ; Gasdermins ; Pyroptosis/physiology ; Inflammasomes ; Caspases/metabolism ; Cytokines/metabolism ; Interleukin-1/metabolism
Chemical Substances	Gasdermins ; Inflammasomes ; Caspases (EC 3.4.22.-) ; Cytokines ; Interleukin-1
Language	English
Publishing date	2023-07-18
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1018141-6
ISSN	1096-3618 ; 1044-5323
ISSN (online)	1096-3618
ISSN	1044-5323
DOI	10.1016/j.smim.2023.101811
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Zs.A 2843: Show issues

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Article ; Online: Optogenetic Induction of Pyroptosis, Necroptosis, and Apoptosis in Mammalian Cell Lines.

Shkarina, Kateryna / Broz, Petr

Bio-protocol

2023 Volume 13, Issue 14, Page(s) e4762

Abstract: Regulated cell death plays a key role in immunity, development, and homeostasis, but is also associated with a number of pathologies such as autoinflammatory and neurodegenerative diseases and cancer. However, despite the extensive mechanistic research ... ...

Abstract	Regulated cell death plays a key role in immunity, development, and homeostasis, but is also associated with a number of pathologies such as autoinflammatory and neurodegenerative diseases and cancer. However, despite the extensive mechanistic research of different cell death modalities, the direct comparison of different forms of cell death and their consequences on the cellular and tissue level remain poorly characterized. Comparative studies are hindered by the mechanistic and kinetic differences between cell death modalities, as well as the inability to selectively induce different cell death programs in an individual cell within cell populations or tissues. In this method, we present a protocol for rapid and specific optogenetic activation of three major types of programmed cell death: apoptosis, necroptosis, and pyroptosis, using light-induced forced oligomerization of their major effector proteins (caspases or kinases).
Language	English
Publishing date	2023-07-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325 ; 2331-8325
ISSN (online)	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.4762
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Article ; Online: Caspase-4 Activation and Recruitment to Intracellular Gram-Negative Bacteria.

Dilucca, Marisa / Broz, Petr

Methods in molecular biology (Clifton, N.J.)

2023 Volume 2641, Page(s) 49–65

Abstract: The non-canonical inflammasome pathway functions as the primary cytosolic innate immune detection mechanism for Gram-negative bacterial lipopolysaccharide (LPS) in human and mouse cells and controls the proteolytic activation of the cell death executor ... ...

Abstract	The non-canonical inflammasome pathway functions as the primary cytosolic innate immune detection mechanism for Gram-negative bacterial lipopolysaccharide (LPS) in human and mouse cells and controls the proteolytic activation of the cell death executor gasdermin D (GSDMD). The main effectors of this pathways are the inflammatory proteases caspase-11 in mice and caspase-4/caspase-5 in humans. These caspases have been shown to bind LPS directly; however, the interaction between LPS and caspase-4/caspase-11 requires a set of interferon (IFN)-inducible GTPases, known as guanylate-binding proteins (GBPs). These GBPs assemble to form coatomers on cytosolic Gram-negative bacteria, which function as recruitment and activation platforms for caspase-11/caspase-4. Here we describe an assay to monitor caspase-4 activation in human cells by immunoblotting and its recruitment to intracellular bacteria using the model pathogen Burkholderia thailandensis.
MeSH term(s)	Humans ; Animals ; Mice ; Lipopolysaccharides/metabolism ; GTP-Binding Proteins/metabolism ; Gram-Negative Bacteria/metabolism ; Caspases/metabolism ; Inflammasomes/metabolism ; Cell Death
Chemical Substances	Lipopolysaccharides ; GTP-Binding Proteins (EC 3.6.1.-) ; Caspases (EC 3.4.22.-) ; Inflammasomes
Language	English
Publishing date	2023-04-19
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-3040-2_5
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Article ; Online: NLRP12 senses heme and PAMPs to drive necrotic cell death and inflammation.

Bernard, Elliott M / Broz, Petr

Molecular cell

2023 Volume 83, Issue 15, Page(s) 2621–2623

Abstract: Red blood cell rupture (hemolysis) activates innate immunity and inflammation by releasing heme. Sundaram et al. ...

Abstract	Red blood cell rupture (hemolysis) activates innate immunity and inflammation by releasing heme. Sundaram et al.
MeSH term(s)	Humans ; Heme/metabolism ; Pathogen-Associated Molecular Pattern Molecules ; Inflammation/metabolism ; Immunity, Innate ; Hemolysis ; Necrosis ; Cell Death ; Intracellular Signaling Peptides and Proteins
Chemical Substances	Heme (42VZT0U6YR) ; Pathogen-Associated Molecular Pattern Molecules ; NLRP12 protein, human ; Intracellular Signaling Peptides and Proteins
Language	English
Publishing date	2023-10-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2023.07.005
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Zs.A 5055: Show issues

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Article ; Online: Selective induction of programmed cell death using synthetic biology tools.

Shkarina, Kateryna / Broz, Petr

Seminars in cell & developmental biology

2023 Volume 156, Page(s) 74–92

Abstract: Regulated cell death (RCD) controls the removal of dispensable, infected or malignant cells, and is thus essential for development, homeostasis and immunity of multicellular organisms. Over the last years different forms of RCD have been described (among ...

Abstract	Regulated cell death (RCD) controls the removal of dispensable, infected or malignant cells, and is thus essential for development, homeostasis and immunity of multicellular organisms. Over the last years different forms of RCD have been described (among them apoptosis, necroptosis, pyroptosis and ferroptosis), and the cellular signaling pathways that control their induction and execution have been characterized at the molecular level. It has also become apparent that different forms of RCD differ in their capacity to elicit inflammation or an immune response, and that RCD pathways show a remarkable plasticity. Biochemical and genetic studies revealed that inhibition of a given pathway often results in the activation of back-up cell death mechanisms, highlighting close interconnectivity based on shared signaling components and the assembly of multivalent signaling platforms that can initiate different forms of RCD. Due to this interconnectivity and the pleiotropic effects of 'classical' cell death inducers, it is challenging to study RCD pathways in isolation. This has led to the development of tools based on synthetic biology that allow the targeted induction of RCD using chemogenetic or optogenetic methods. Here we discuss recent advances in the development of such toolset, highlighting their advantages and limitations, and their application for the study of RCD in cells and animals.
MeSH term(s)	Animals ; Synthetic Biology ; Apoptosis/physiology ; Cell Death ; Pyroptosis/genetics ; Signal Transduction
Language	English
Publishing date	2023-08-17
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1312473-0
ISSN	1096-3634 ; 1084-9521
ISSN (online)	1096-3634
ISSN	1084-9521
DOI	10.1016/j.semcdb.2023.07.012
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Zs.A 2918: Show issues

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Article ; Online: Recognition of Intracellular Bacteria by Inflammasomes.

Broz, Petr

Microbiology spectrum

2019 Volume 7, Issue 2

Abstract: Inflammasomes are multiprotein signaling complexes that are assembled by cytosolic sensors upon the detection of infectious or noxious stimuli. These complexes activate inflammatory caspases to induce host cell death and cytokine secretion and are an ... ...

Abstract	Inflammasomes are multiprotein signaling complexes that are assembled by cytosolic sensors upon the detection of infectious or noxious stimuli. These complexes activate inflammatory caspases to induce host cell death and cytokine secretion and are an essential part of antimicrobial host defense. In this review, I discuss how intracellular bacteria are detected by inflammasomes, how the specific sensing mechanism of each inflammasome receptor restricts the ability of bacteria to evade immune recognition, and how host cell death is used to control bacterial replication
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Anti-Infective Agents/pharmacology ; Apoptosis Regulatory Proteins/metabolism ; Bacteria/isolation & purification ; Bacteria/pathogenicity ; CARD Signaling Adaptor Proteins/metabolism ; Calcium-Binding Proteins/metabolism ; Cell Death ; Cytokines/metabolism ; Cytosol/microbiology ; DNA-Binding Proteins/metabolism ; Humans ; Immune Evasion ; Inflammasomes/immunology ; Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Neuronal Apoptosis-Inhibitory Protein/metabolism ; Pyrin/metabolism ; Pyroptosis/drug effects ; Signal Transduction/immunology
Chemical Substances	AIM2 protein, human ; Adaptor Proteins, Signal Transducing ; Anti-Infective Agents ; Apoptosis Regulatory Proteins ; CARD Signaling Adaptor Proteins ; Calcium-Binding Proteins ; Cytokines ; DNA-Binding Proteins ; Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein ; NLRC4 protein, human ; NLRP1 protein, human ; Neuronal Apoptosis-Inhibitory Protein ; Pyrin
Language	English
Publishing date	2019-03-01
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2165-0497
ISSN (online)	2165-0497
DOI	10.1128/microbiolspec.BAI-0003-2019
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Article ; Online: Activation and manipulation of inflammasomes and pyroptosis during bacterial infections.

Bernard, Elliott M / Broz, Petr

The Biochemical journal

2022 Volume 479, Issue 7, Page(s) 867–882

Abstract: Following detection of pathogen infection and disrupted cellular homeostasis, cells can activate a range of cell death pathways, such as apoptosis, necroptosis and pyroptosis, as part of their defence strategy. The initiation of pro-inflammatory, lytic ... ...

Abstract	Following detection of pathogen infection and disrupted cellular homeostasis, cells can activate a range of cell death pathways, such as apoptosis, necroptosis and pyroptosis, as part of their defence strategy. The initiation of pro-inflammatory, lytic pyroptosis is controlled by inflammasomes, which respond to a range of cellular perturbations. As is true for many host defence pathways, pathogens have evolved multiple mechanisms to subvert this pathway, many of which have only recently been described. Herein, we will discuss the mechanisms by which inflammasomes sense pathogen invasion and initiate pyroptosis and the effector mechanisms used by pathogens to suppress this pathway and preserve their niche.
MeSH term(s)	Apoptosis ; Bacterial Infections ; Cell Death ; Humans ; Inflammasomes/metabolism ; Pyroptosis
Chemical Substances	Inflammasomes
Language	English
Publishing date	2022-05-11
Publishing country	England
Document type	Journal Article ; 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/BCJ20220051
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Article ; Online: National Genome Initiatives in Europe and the United Kingdom in the Era of Whole-Genome Sequencing: A Comprehensive Review.

Smetana, Jan / Brož, Petr

Genes

2022 Volume 13, Issue 3

Abstract: Identification of genomic variability in population plays an important role in the clinical diagnostics of human genetic diseases. Thanks to rapid technological development in the field of massive parallel sequencing technologies, also known as next- ... ...

Abstract	Identification of genomic variability in population plays an important role in the clinical diagnostics of human genetic diseases. Thanks to rapid technological development in the field of massive parallel sequencing technologies, also known as next-generation sequencing (NGS), complex genomic analyses are now easier and cheaper than ever before, which consequently leads to more effective utilization of these techniques in clinical practice. However, interpretation of data from NGS is still challenging due to several issues caused by natural variability of DNA sequences in human populations. Therefore, development and realization of projects focused on description of genetic variability of local population (often called "national or digital genome") with a NGS technique is one of the best approaches to address this problem. The next step of the process is to share such data via publicly available databases. Such databases are important for the interpretation of variants with unknown significance or (likely) pathogenic variants in rare diseases or cancer or generally for identification of pathological variants in a patient's genome. In this paper, we have compiled an overview of published results of local genome sequencing projects from United Kingdom and Europe together with future plans and perspectives for newly announced ones.
MeSH term(s)	Genomics/methods ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Neoplasms/genetics ; United Kingdom ; Whole Genome Sequencing
Language	English
Publishing date	2022-03-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13030556
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Article ; Online: Viral protein activates the NLRP1 inflammasome.

Hartenian, Ella / Broz, Petr

Nature immunology

2022 Volume 23, Issue 6, Page(s) 822–824

MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Apoptosis Regulatory Proteins/metabolism ; Inflammasomes/metabolism ; Viral Proteins/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Apoptosis Regulatory Proteins ; Inflammasomes ; Viral Proteins
Language	English
Publishing date	2022-05-26
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-022-01226-x
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Zs.A 5294: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: National Genome Initiatives in Europe and the United Kingdom in the Era of Whole-Genome Sequencing: A Comprehensive Review

Smetana, Jan / Brož, Petr

Genes. 2022 Mar. 21, v. 13, no. 3

2022

Abstract	Identification of genomic variability in population plays an important role in the clinical diagnostics of human genetic diseases. Thanks to rapid technological development in the field of massive parallel sequencing technologies, also known as next-generation sequencing (NGS), complex genomic analyses are now easier and cheaper than ever before, which consequently leads to more effective utilization of these techniques in clinical practice. However, interpretation of data from NGS is still challenging due to several issues caused by natural variability of DNA sequences in human populations. Therefore, development and realization of projects focused on description of genetic variability of local population (often called “national or digital genome”) with a NGS technique is one of the best approaches to address this problem. The next step of the process is to share such data via publicly available databases. Such databases are important for the interpretation of variants with unknown significance or (likely) pathogenic variants in rare diseases or cancer or generally for identification of pathological variants in a patient’s genome. In this paper, we have compiled an overview of published results of local genome sequencing projects from United Kingdom and Europe together with future plans and perspectives for newly announced ones.
Keywords	DNA ; diagnostic techniques ; genetic variation ; genomics ; humans ; patients ; United Kingdom
Language	English
Dates of publication	2022-0321
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13030556
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