CASP1 variants influence subcellular caspase-1 localization, pyroptosome formation, pro-inflammatory cell death and macrophage deformability

CASP1 variants influence subcellular caspase-1 localization, pyroptosome formation, pro-inflammatory cell death and macrophage deformability

Copyright © 2019 Elsevier Inc. All rights reserved.

Bibliographische Detailangaben
Veröffentlicht in:Clinical immunology (Orlando, Fla.). - 1999. - 208(2019) vom: 15. Nov., Seite 108232
1. Verfasser: Kapplusch, Franz (VerfasserIn)
Weitere Verfasser: Schulze, Felix, Rabe-Matschewsky, Sabrina, Russ, Susanne, Herbig, Maik, Heymann, Michael Christian, Schoepf, Katharina, Stein, Robert, Range, Ursula, Rösen-Wolff, Angela, Winkler, Stefan, Hedrich, Christian Michael, Guck, Jochen, Hofmann, Sigrun Ruth
Format: Online-Aufsatz
Sprache:English
Veröffentlicht: 2019
Zugriff auf das übergeordnete Werk:Clinical immunology (Orlando, Fla.)
Schlagworte:Journal Article Research Support, Non-U.S. Gov't Apoptosis-associated speck-like protein containing a CARD (ASC) Caspase-1 Gasdermin D IL-1β Inflammasome Interleukin-1 converting enzyme NLRP3 Pyroptosis mehr... Pyroptosome Speck Inflammasomes Caspase 1 EC 3.4.22.36
Beschreibung
Zusammenfassung:Copyright © 2019 Elsevier Inc. All rights reserved.
CASP1 variants result in reduced enzymatic activity of procaspase-1 and impaired IL-1β release. Despite this, affected individuals can develop systemic autoinflammatory disease. These seemingly contradictory observations have only partially been explained by increased NF-κB activation through prolonged interaction of variant procaspase-1 with RIP2. To identify further disease underlying pathomechanisms, we established an in vitro model using shRNA-directed knock-down of procaspase-1 followed by viral transduction of human monocytes (THP-1) with plasmids encoding for wild-type procaspase-1, disease-associated CASP1 variants (p.L265S, p.R240Q) or a missense mutation in the active center of procaspase-1 (p.C285A). THP1-derived macrophages carrying CASP1 variants exhibited mutation-specific molecular alterations. We here provide in vitro evidence for abnormal pyroptosome formation (p.C285A, p.240Q, p.L265S), impaired nuclear (pro)caspase-1 localization (p.L265S), reduced pro-inflammatory cell death (p.C285A) and changes in macrophage deformability that may contribute to disease pathophysiology of patients with CASP1 variants. This offers previously unknown molecular pathomechanisms in patients with systemic autoinflammatory disease
Beschreibung:Date Completed 19.05.2020
Date Revised 19.05.2020
published: Print-Electronic
Citation Status MEDLINE
ISSN:1521-7035
DOI:10.1016/j.clim.2019.06.008