title: Cutting edge: SHARPIN is required for optimal NLRP3 inflammasome activation.
abstract: The NLRP3 inflammasome is a multimeric protein complex that is assembled in response to a wide array of pathogens and danger-associated molecular patterns. Despite the ability of NLRP3 to respond to diverse cues, the mechanisms controlling the assembly of this complex are contested. Recently published studies showed that HOIL-1, a member of the linear ubiquitin chain assembly complex, contributes to activation of the NLRP3 inflammasome. SHARPIN, along with HOIP and HOIL-1, constitute the linear ubiquitin chain assembly complex. In this study, we examined whether SHARPIN is required for the activation of the NLRP3 inflammasome. Using Sharpin(cpdm) macrophages (deficient in SHARPIN expression), we demonstrate that SHARPIN is required for optimal activation of the NLRP3 inflammasome by both canonical and noncanonical stimuli. Furthermore, Sharpin(cpdm) macrophages had dramatic defects on both the NF-κB and MAPK pathways, suggesting a role in transcriptional priming of the NLRP3 inflammasome. In conclusion, our study identified SHARPIN as a novel regulator of the NLRP3 inflammasome.
authors: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors: Prajwal
authors: P
authors: Gurung
authors: Department of Medical Protein Research, Flanders Institute of Biotechnology, Ghent B-9000, Belgium; and Department of Biochemistry, Ghent University, Ghent B-9000, Belgium.
authors: Mohamed
authors: M
authors: Lamkanfi
authors: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105; Thirumala-Devi.Kanneganti@StJude.org.
authors: Thirumala-Devi
authors: TD
authors: Kanneganti
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015398:Signal Transduction; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000235:genetics / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C554944:Sipl1 protein, mouse; D025801:Ubiquitin; C492590:Rnf31 protein, mouse; D044767:Ubiquitin-Protein Ligases; D020928:Mitogen-Activated Protein Kinases
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