GSDMB promotes non-canonical pyroptosis by enhancing caspase-4 activity

Abstract Gasdermin B (GSDMB) has been reported to be associated with immune diseases in humans, but the detailed molecular mechanisms remain unsolved. The N-terminus of GSDMB by itself, unlike other gasdermin family proteins, does not induce cell death. Here, we show that GSDMB is highly expressed in the leukocytes of septic shock patients, which is associated with increased release of the gasdermin D (GSDMD) N-terminus. GSDMB expression and the accumulation of the N-terminal fragment of GSDMD are induced by the activation of the non-canonical pyroptosis pathway in a human monocyte cell line. The downregulation of GSDMB alleviates the cleavage of GSDMD and cell death. Consistently, the overexpression of GSDMB promotes GSDMD cleavage, accompanied by increased LDH release. We further found that GSDMB promotes caspase-4 activity, which is required for the cleavage of GSDMD in non-canonical pyroptosis, by directly binding to the CARD domain of caspase-4. Our study reveals a GSDMB-mediated novel regulatory mechanism for non-canonical pyroptosis and suggests a potential new strategy for the treatment of inflammatory diseases.

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LPS Stimulation of Complement (C3) Synthesis by a Human Monocyte Cell Line

Complement ◽

10.1159/000467823 ◽

1984 ◽

Vol 1 (2) ◽

pp. 108-115 ◽

Cited By ~ 11

Author(s):

William K. Nichols

Keyword(s):

Cell Line ◽

Human Monocyte ◽

Complement C3 ◽

Human Monocyte Cell Line ◽

Monocyte Cell ◽

Stimulation Of

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Human monocyte cell line (U937) releases suppressive IgG-binding factor(s)

European Journal of Immunology ◽

10.1002/eji.1830160106 ◽

1986 ◽

Vol 16 (1) ◽

pp. 25-30 ◽

Cited By ~ 15

Author(s):

Charles Félix Calvo ◽

Shinichiro Watanabe ◽

Didier Mètivier ◽

Anna Senik

Keyword(s):

Cell Line ◽

Human Monocyte ◽

Igg Binding ◽

Binding Factor ◽

Human Monocyte Cell Line ◽

Monocyte Cell

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Inhibition by costunolide of phorbol ester-induced transcriptional activation of inducible nitric oxide synthase gene in a human monocyte cell line THP-1

Cancer Letters ◽

10.1016/s0304-3835(00)00704-7 ◽

2001 ◽

Vol 164 (1) ◽

pp. 7-13 ◽

Cited By ~ 25

Author(s):

Kazunori Fukuda ◽

Seigou Akao ◽

Yasushi Ohno ◽

Kazuya Yamashita ◽

Hisayoshi Fujiwara

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Phorbol Ester ◽

Transcriptional Activation ◽

Human Monocyte ◽

Human Monocyte Cell Line ◽

Monocyte Cell ◽

Oxide Synthase ◽

Inducible Nitric Oxide

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The inhibitory effect of fluvastatin, an HMG-CoA reductase inhibitor, on the expression of adhesion molecules on human monocyte cell line.

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)37458-x ◽

1996 ◽

Vol 71 ◽

pp. 305

Author(s):

Satoru Niwa ◽

Tetsuya Totsuka ◽

Shigehiro Hayashi

Keyword(s):

Cell Line ◽

Adhesion Molecules ◽

Reductase Inhibitor ◽

Human Monocyte ◽

Inhibitory Effect ◽

Hmg Coa Reductase ◽

Human Monocyte Cell Line ◽

Monocyte Cell ◽

Hmg Coa Reductase Inhibitor ◽

Coa Reductase

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Current translational potential and underlying molecular mechanisms of necroptosis

Cell Death and Disease ◽

10.1038/s41419-019-2094-z ◽

2019 ◽

Vol 10 (11) ◽

Cited By ~ 14

Author(s):

Tamás Molnár ◽

Anett Mázló ◽

Vera Tslaf ◽

Attila Gábor Szöllősi ◽

Gabriella Emri ◽

...

Keyword(s):

Cell Death ◽

Protein Kinase ◽

Posttranslational Modifications ◽

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Immune Surveillance ◽

Kinase Domain ◽

Tumor Formation

Abstract Cell death has a fundamental impact on the evolution of degenerative disorders, autoimmune processes, inflammatory diseases, tumor formation and immune surveillance. Over the past couple of decades extensive studies have uncovered novel cell death pathways, which are independent of apoptosis. Among these is necroptosis, a tightly regulated, inflammatory form of cell death. Necroptosis contribute to the pathogenesis of many diseases and in this review, we will focus exclusively on necroptosis in humans. Necroptosis is considered a backup mechanism of apoptosis, but the in vivo appearance of necroptosis indicates that both caspase-mediated and caspase-independent mechanisms control necroptosis. Necroptosis is regulated on multiple levels, from the transcription, to the stability and posttranslational modifications of the necrosome components, to the availability of molecular interaction partners and the localization of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL). Accordingly, we classified the role of more than seventy molecules in necroptotic signaling based on consistent in vitro or in vivo evidence to understand the molecular background of necroptosis and to find opportunities where regulating the intensity and the modality of cell death could be exploited in clinical interventions. Necroptosis specific inhibitors are under development, but >20 drugs, already used in the treatment of various diseases, have the potential to regulate necroptosis. By listing necroptosis-modulated human diseases and cataloging the currently available drug-repertoire to modify necroptosis intensity, we hope to kick-start approaches with immediate translational potential. We also indicate where necroptosis regulating capacity should be considered in the current applications of these drugs.

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Ultrastructural Analysis of Beta-Amyloid Production in Monocytes, Astrocytes, Epithelial, and Endothelial Cells Infected with Chlamydia Pneumoniae Isolated from Alzheimer Brains

Microscopy and Microanalysis ◽

10.1017/s1431927600035832 ◽

2000 ◽

Vol 6 (S2) ◽

pp. 668-669

Author(s):

C.S. Little ◽

A. Maclntyre ◽

C. Hammond ◽

E. Venuti ◽

B.J. Bromke ◽

...

Keyword(s):

Chlamydia Pneumoniae ◽

Infectious Agent ◽

Human Monocyte ◽

Beta Amyloid ◽

Host Cells ◽

Rt Pcr ◽

Sporadic Alzheimer’S Disease ◽

Human Monocyte Cell Line ◽

Monocyte Cell ◽

The Brain

Previously, we uncovered evidence of an infectious agent, Chlamydia pneumoniae, associated with sporadic Alzheimer's disease (AD). We demonstrated that C. pneumoniae was present in 90% of brain materials examined from AD patients, compared with 5% in age-matched, non-AD patients. We further showed that microglia and astroglia in the CNS are host cells for the bacterium. RT-PCR analyses indicated that the bacterium is metabolically-active in the brain and could be cultured in a human monocyte cell line (THP-1). Importantly, we showed that the organism is concentrated in areas of AD-neuropathology also containing tau and beta-amyloid. The present study was designed to investigate the effects of C. pneumoniae infection on beta amyloid production in human monocytes (THP-1), astroglial (CCF-STTG1), epithelial (Hep 2), and endothelial (HBMEC) cell lines. We investigated the host pathogen relationship with C. pneumoniae and whether entities characteristic of AD neuropathology such as betaamyloid are associated directly with this infectious agent.

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