scholarly journals PHOrming the inflammasome: phosphorylation is a critical switch in inflammasome signalling

2021 ◽  
Author(s):  
Chloe M. McKee ◽  
Fabian A. Fischer ◽  
Jelena S. Bezbradica ◽  
Rebecca C. Coll
Keyword(s):  
Cell Death ◽  
Protein Function ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Protein Complexes ◽  
Inflammasome Activation ◽  
Subcellular Localisation ◽  
Adapter Proteins ◽  
Post Translational Modification ◽  
And Function

Inflammasomes are protein complexes in the innate immune system that regulate the production of pro-inflammatory cytokines and inflammatory cell death. Inflammasome activation and subsequent cell death often occur within minutes to an hour, so the pathway must be dynamically controlled to prevent excessive inflammation and the development of inflammatory diseases. Phosphorylation is a fundamental post-translational modification that allows rapid control over protein function and the phosphorylation of inflammasome proteins has emerged as a key regulatory step in inflammasome activation. Phosphorylation of inflammasome sensor and adapter proteins regulates their inter- and intra-molecular interactions, subcellular localisation, and function. The control of inflammasome phosphorylation may thus provide a new strategy for the development of anti-inflammatory therapeutics. Herein we describe the current knowledge of how phosphorylation operates as a critical switch for inflammasome signalling.

scholarly journals Mutual Interplay of Host Immune System and Gut Microbiota in the Immunopathology of Atherosclerosis

2020 ◽  
Vol 21 (22) ◽  
pp. 8729 ◽  
Author(s):  
Chih-Fan Yeh ◽  
Ying-Hsien Chen ◽  
Sheng-Fu Liu ◽  
Hsien-Li Kao ◽  
Ming-Shiang Wu ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Cytokine Production ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Inflammasome Activation ◽  
Host Immune System ◽  
Gut Permeability ◽  
And Function ◽  
Progression Of Atherosclerosis

Inflammation is the key for the initiation and progression of atherosclerosis. Accumulating evidence has revealed that an altered gut microbiome (dysbiosis) triggers both local and systemic inflammation to cause chronic inflammatory diseases, including atherosclerosis. There have been some microbiome-relevant pro-inflammatory mechanisms proposed to link the relationships between dysbiosis and atherosclerosis such as gut permeability disruption, trigger of innate immunity from lipopolysaccharide (LPS), and generation of proatherogenic metabolites, such as trimethylamine N-oxide (TMAO). Meanwhile, immune responses, such as inflammasome activation and cytokine production, could reshape both composition and function of the microbiota. In fact, the immune system delicately modulates the interplay between microbiota and atherogenesis. Recent clinical trials have suggested the potential of immunomodulation as a treatment strategy of atherosclerosis. Here in this review, we present current knowledge regarding to the roles of microbiota in contributing atherosclerotic pathogenesis and highlight translational perspectives by discussing the mutual interplay between microbiota and immune system on atherogenesis.

scholarly journals The Molecular Links between Cell Death and Inflammasome

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1057 ◽  
Author(s):  
Kwang-Ho Lee ◽  
Tae-Bong Kang
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Death Receptor ◽  
Signaling Molecules ◽  
Inflammasome Activation ◽  
Cell Death Pathways ◽  
Wide Range ◽  
Activation Pathways

Programmed cell death pathways and inflammasome activation pathways can be genetically and functionally separated. Inflammasomes are specialized protein complexes that process pro-inflammatory cytokines, interleukin-1β (IL-1β), and IL-18 to bioactive forms for protection from a wide range of pathogens, as well as environmental and host-derived danger molecules. Programmed cell death has been extensively studied, and its role in the development, homeostasis, and control of infection and danger is widely appreciated. Apoptosis and the recently recognized necroptosis are the best-characterized forms of programmed death, and the interplay between them through death receptor signaling is also being studied. Moreover, growing evidence suggests that many of the signaling molecules known to regulate programmed cell death can also modulate inflammasome activation in a cell-intrinsic manner. Therefore, in this review, we will discuss the current knowledge concerning the role of the signaling molecules originally associated with programmed cell death in the activation of inflammasome and IL-1β processing.

scholarly journals iProteinDB: an integrative database of Drosophila post-translational modifications

2018 ◽  
Author(s):  
Yanhui Hu ◽  
Richelle Sopko ◽  
Verena Chung ◽  
Romain A. Studer ◽  
Sean D. Landry ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Function ◽  
Large Scale ◽  
Model Organisms ◽  
General Strategy ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Functional Sites ◽  
Evolutionarily Conserved ◽  
And Function

AbstractPost-translational modification (PTM) serves as a regulatory mechanism for protein function, influencing stability, protein interactions, activity and localization, and is critical in many signaling pathways. The best characterized PTM is phosphorylation, whereby a phosphate is added to an acceptor residue, commonly serine, threonine and tyrosine. As proteins are often phosphorylated at multiple sites, identifying those sites that are important for function is a challenging problem. Considering that many phosphorylation sites may be non-functional, prioritizing evolutionarily conserved phosphosites provides a general strategy to identify the putative functional sites with regards to regulation and function. To facilitate the identification of conserved phosphosites, we generated a large-scale phosphoproteomics dataset from Drosophila embryos collected from six closely-related species. We built iProteinDB (https://www.flyrnai.org/tools/iproteindb/), a resource integrating these data with other high-throughput PTM datasets, including vertebrates, and manually curated information for Drosophila. At iProteinDB, scientists can view the PTM landscape for any Drosophila protein and identify predicted functional phosphosites based on a comparative analysis of data from closely-related Drosophila species. Further, iProteinDB enables comparison of PTM data from Drosophila to that of orthologous proteins from other model organisms, including human, mouse, rat, Xenopus laevis, Danio rerio, and Caenorhabditis elegans.

scholarly journals Cannabinoids as Key Regulators of Inflammasome Signaling: A Current Perspective

2021 ◽  
Vol 11 ◽  
Author(s):  
Santosh V. Suryavanshi ◽  
Igor Kovalchuk ◽  
Olga Kovalchuk
Keyword(s):  
Cannabis Sativa ◽  
Inflammatory Diseases ◽  
Protein Complexes ◽  
Synthetic Cannabinoids ◽  
Inflammasome Activation ◽  
Published Evidence ◽  
Current Perspective ◽  
Novel Drugs ◽  
Human Disorders ◽  
Pharmacologically Active

Inflammasomes are cytoplasmic inflammatory signaling protein complexes that detect microbial materials, sterile inflammatory insults, and certain host-derived elements. Inflammasomes, once activated, promote caspase-1–mediated maturation and secretion of pro-inflammatory cytokines, interleukin (IL)-1β and IL-18, leading to pyroptosis. Current advances in inflammasome research support their involvement in the development of chronic inflammatory disorders in contrast to their role in regulating innate immunity. Cannabis (marijuana) is a natural product obtained from the Cannabis sativa plant, and pharmacologically active ingredients of the plant are referred to as cannabinoids. Cannabinoids and cannabis extracts have recently emerged as promising novel drugs for chronic medical conditions. Growing evidence indicates the potent anti-inflammatory potential of cannabinoids, especially Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and synthetic cannabinoids; however, the mechanisms remain unclear. Several attempts have been made to decipher the role of cannabinoids in modulating inflammasome signaling in the etiology of chronic inflammatory diseases. In this review, we discuss recently published evidence on the effect of cannabinoids on inflammasome signaling. We also discuss the contribution of various cannabinoids in human diseases concerning inflammasome regulation. Lastly, in the milieu of coronavirus disease-2019 (COVID-19) pandemic, we confer available evidence linking inflammasome activation to the pathophysiology of COVID-19 suggesting overall, the importance of cannabinoids as possible drugs to target inflammasome activation in or to support the treatment of a variety of human disorders including COVID-19.

The roles of peptidyl-proline isomerases in gene regulation1This review is part of Special Issue entitled Asilomar Chromatin and has undergone the Journal’s usual peer review process.

2012 ◽  
Vol 90 (1) ◽  
pp. 55-69 ◽  
Author(s):  
David Dilworth ◽  
Geoff Gudavicius ◽  
Andrew Leung ◽  
Christopher J. Nelson
Keyword(s):  
Protein Function ◽  
Peer Review Process ◽  
Post Translational Modification ◽  
Multiple Control ◽  
Proline Isomerization ◽  
Evolutionarily Conserved ◽  
Covalent Modifications ◽  
And Function ◽  
Fk506 Binding Proteins ◽  
Substrate Proteins

The post-translational modification of proteins and enzymes provides a dynamic and reversible means to control protein function and transmit biological signals. While covalent modifications such as phosphorylation and acetylation have drawn much attention, in the past decade the involvement of peptidyl-proline isomerases (PPIs) in signaling and post-translational modification of protein function has become increasingly apparent. Three distinct families of PPI enzymes (parvulins, cyclophilins, and FK506-binding proteins (FKBPs)) each have the capacity to catalyze cis–trans proline isomerization in substrate proteins, and this modification can regulate both structure and function. In eukaryotic cells, a subset of these enzymes is localized to the nucleus, where they regulate gene expression at multiple control points. Here we summarize this body of work that together establishes a clear role of these enzymes as evolutionarily conserved players in the control of both transcription of mRNAs and the assembly of chromatin.

Composition and function of PDZ protein complexes during cell polarization

2003 ◽  
Vol 285 (3) ◽  
pp. F377-F387 ◽  
Author(s):  
Michael H. Roh ◽  
Ben Margolis
Keyword(s):  
Epithelial Cells ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Cell Types ◽  
Cell Polarization ◽  
Differential Distribution ◽  
Pdz Proteins ◽  
Homologous Protein ◽  
Pdz Protein ◽  
And Function

Complexes consisting of PDZ proteins have been implicated in a variety of cellular processes. In recent years, it has become increasingly clear that PDZ proteins play essential roles during the establishment of spatial asymmetry in various metazoan cell types such as epithelial cells. Epithelial cells possess asymmetry with respect to the apicobasal axis reflected by the differential distribution of proteins and lipids in the apical and basolateral surfaces. In Drosophila, three PDZ protein complexes have been shown to play crucial functions during the establishment of cell-cell adhesions and epithelial cell polarity: Bazooka/Dm-Par6/DaPKC, Crumbs/Stardust/Discs Lost, and Scribble/Discs Large/Lethal Giant Larvae. In this review, we focus primarily on our current knowledge of the localization and function of these complexes in Drosophila epithelia. We also discuss recent data that enhance our understanding of the homologous protein complexes and their roles during junctional assembly and polarization of mammalian epithelial cells.

Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome

2016 ◽  
Vol 397 (12) ◽  
pp. 1315-1333 ◽  
Author(s):  
Isabel Meininger ◽  
Daniel Krappmann
Keyword(s):  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Antigen Receptor ◽  
Lymphocyte Activation ◽  
Downstream Signaling ◽  
Antigen Receptor Signaling ◽  
Autoimmune And Inflammatory Diseases ◽  
And Function

Abstract The CARMA1-BCL10-MALT1 (CBM) signalosome triggers canonical NF-κB signaling and lymphocyte activation upon antigen-receptor stimulation. Genetic studies in mice and the analysis of human immune pathologies unveiled a critical role of the CBM complex in adaptive immune responses. Great progress has been made in elucidating the fundamental mechanisms that dictate CBM assembly and disassembly. By bridging proximal antigen-receptor signaling to downstream signaling pathways, the CBM complex exerts a crucial scaffolding function. Moreover, the MALT1 subunit confers a unique proteolytic activity that is key for lymphocyte activation. Deregulated ‘chronic’ CBM signaling drives constitutive NF-κB signaling and MALT1 activation, which contribute to the development of autoimmune and inflammatory diseases as well as lymphomagenesis. Thus, the processes that govern CBM activation and function are promising targets for the treatment of immune disorders. Here, we summarize the current knowledge on the functions and mechanisms of CBM signaling in lymphocytes and how CBM deregulations contribute to aberrant signaling in malignant lymphomas.

scholarly journals New insights in caspase-11 functions in noncanonical inflammasome signalling

Inflammasome ◽  
2014 ◽  
Vol 1 (1) ◽  
Author(s):  
Mélanie Bodnar ◽  
Virginie Petrilli
Keyword(s):  
Cell Death ◽  
Inflammatory Cell ◽  
Protein Complexes ◽  
Inflammasome Activation ◽  
Gram Negative Bacteria ◽  
Nucleotide Binding Domain ◽  
Gram Negative ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Dependent Pathway

AbstractInflammasomes are multi-protein complexes that play a crucial role in innate immunity. They are assembled by cytosolic sensors of the Nucleotide-binding domain and Leucine-rich repeat containing Receptor (NLR) and PYrin and HIN (PYHIN) domain-containing protein families upon sensing various pathogens and danger signals. Inflammasome formation culminates in caspase-1 activation, which causes the cleavage of pro-IL-1β and pro- IL-18 into active cytokines; this eventually results in the induction of an inflammatory cell death called pyroptosis. Recent data using Gram-negative bacteria suggests a role for caspase-11 not only in NLRP3 inflammasome activation but also in a caspase-1- and inflammasome-independent cell death. This novel caspase-11-dependent pathway is critical to control infection by Gram-negative bacteria and has been named the noncanonical inflammasome.

scholarly journals Recent insights into the regulatory networks of NLRP3 inflammasome activation

2020 ◽  
Vol 133 (23) ◽  
pp. jcs248344 ◽  
Author(s):  
Alexander N. R. Weber ◽  
Zsófia A. Bittner ◽  
Sangeetha Shankar ◽  
Xiao Liu ◽  
Tzu-Hsuan Chang ◽  
...  
Keyword(s):  
Cell Death ◽  
Nlrp3 Inflammasome ◽  
Regulatory Networks ◽  
Proteolytic Processing ◽  
Inflammasome Activation ◽  
Post Translational Modification ◽  
Cell Death Pathways ◽  
Open Questions ◽  
Cellular Machinery ◽  
Death Effector

ABSTRACTThe NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is a fascinating cellular machinery endowed with the capacity for rapid proteolytic processing of the pro-inflammatory cytokine IL-1β and the cell death effector gasdermin D (GSDMD). Although its activity is essential to fight infection and support tissue homeostasis, the inflammasome complex, which consists of the danger sensor NLRP3, the adaptor apoptosis-associated speck-like protein containing a CARD (ASC; also known as PYCARD), caspase-1 and probably other regulatory proteins, also bears considerable potential for detrimental inflammation, as observed in human conditions such as gout, heart attack, stroke and Alzheimer's disease. Thus, multi-layered regulatory networks are required to ensure the fine balance between rapid responsiveness versus erroneous activation (sufficient and temporally restricted versus excessive and chronic activity) of the inflammasome. These involve multiple activation, secretion and cell death pathways, as well as modulation of the subcellular localization of NLRP3, and its structure and activity, owing to post-translational modification by other cellular proteins. Here, we discuss the exciting progress that has recently been made in deciphering the regulation of the NLRP3 inflammasome. Additionally, we highlight open questions and describe areas of research that warrant further exploration to obtain a more comprehensive molecular and cellular understanding of the NLRP3 inflammasome.

scholarly journals Inflammasome Activation in Pulmonary Arterial Hypertension

2022 ◽  
Vol 8 ◽  
Author(s):  
Anna Foley ◽  
Benjamin E. Steinberg ◽  
Neil M. Goldenberg
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Inflammasome Activation ◽  
Downstream Effectors ◽  
Inflammatory Stimuli ◽  
Affected Tissue ◽  
Pulmonary Arterial

Inflammasomes are multi-protein complexes that sense both infectious and sterile inflammatory stimuli, launching a cascade of responses to propagate danger signaling throughout an affected tissue. Recent studies have implicated inflammasome activation in a variety of pulmonary diseases, including pulmonary arterial hypertension (PAH). Indeed, the end-products of inflammasome activation, including interleukin (IL)-1β, IL-18, and lytic cell death (“pyroptosis”) are all key biomarkers of PAH, and are potentially therapeutic targets for human disease. This review summarizes current knowledge of inflammasome activation in immune and vascular cells of the lung, with a focus on the role of these pathways in the pathogenesis of PAH. Special emphasis is placed on areas of potential drug development focused on inhibition of inflammasomes and their downstream effectors.

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