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      Recent insights into the regulatory networks of NLRP3 inflammasome activation

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          ABSTRACT

          The 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.

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          Interleukin-1 beta maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity.

          Lipopolysaccharide (LPS)-stimulated mouse peritoneal macrophages produce large quantities of interleukin (IL)-1 beta but in the absence of a secondary stimulus little of this cytokine is proteolytically processed to its mature biologically active state and externalized. The potassium-proton ionophore nigericin and ATP are known to promote the maturation and release of IL-1 beta from LPS-stimulated cells. We investigated the mechanisms by which these agents act in an attempt to understand requirements of the post-translational processing. Like nigericin, the ionophores A204 and lasalocid induced the release and maturation of IL-1 beta. The electrogenic potassium ionophore valinomycin, however, did not stimulate these post-translational events. Addition of nigericin or lasalocid to LPS-stimulated cells produced a rapid intracellular acidification; A204, however, did not alter pH, indicating that an acidification was not necessary for activation of IL-1 beta maturation. Macrophages treated with ATP became rounded and swollen, and after 30 min of treatment their appearance was comparable with cells treated with nigericin. Post-translational maturation and release of IL-1 beta began immediately after ATP addition. The majority of the 17-kDa mature IL-1 beta produced within the first 30 min of treatment was recovered extracellularly; in contrast, during this same time period the 35-kDa IL-1 beta precursor and the cytoplasmic marker enzyme lactate dehydrogenase and the lysosomal enzyme beta-N-acetylglucosaminidase remained cell-associated. ATP, therefore, promoted both the proteolytic maturation of IL-1 beta and the release of the biologically active species in the absence of cell lysis. Longer incubations with ATP caused cytolysis as judged by the release of the cytoplasmic enzymes. ADP was less active than ATP at initiating the post-translational maturation and release of IL-1 beta and AMP, GTP, and UTP were totally inactive, ATP, nigericin, A204, and lasalocid promoted a rapid and complete loss of the potassium analog 86Rb+ from cells that were preloaded with this cation; valinomycin-treated cells released only a portion of the radiolabeled cation. Agents that promoted the maturation and release of IL-1 beta from LPS-stimulated macrophages, therefore, shared an ability to mobilize intracellular potassium. Macrophages treated with ATP or nigericin in medium that contained KCl rather than NaCl failed to proteolytically activate and to release IL-1 beta. These data suggest that ATP and nigericin induce a net decrease in intracellular levels of K+ which is necessary for activation of the post-translational maturation of IL-1 beta.
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            Author and article information

            Contributors
            (View ORCID Profile)
            Journal
            Journal of Cell Science
            J Cell Sci
            The Company of Biologists
            0021-9533
            1477-9137
            December 03 2020
            December 01 2020
            December 03 2020
            December 01 2020
            : 133
            : 23
            : jcs248344
            Affiliations
            [1 ]Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany
            [2 ]iFIT – Cluster of Excellence (EXC 2180) ‘Image-Guided and Functionally Instructed Tumor Therapies’, University Hospital Tübingen - Internal Medicine VIII, Otfried-Müller-Str. 14, 72076 Tübingen, Germany
            [3 ]Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026 China
            Article
            10.1242/jcs.248344
            33273068
            3fc3127a-18b5-4ec8-a373-1cfff13c13fa
            © 2020

            http://www.biologists.com/user-licence-1-1

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