دورية أكاديمية
أعرض في EDS

Antagonistic nanobodies implicate mechanism of GSDMD pore formation and potential therapeutic application.

التفاصيل البيبلوغرافية
العنوان: Antagonistic nanobodies implicate mechanism of GSDMD pore formation and potential therapeutic application.
المؤلفون: Schiffelers LDJ; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany., Tesfamariam YM; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany., Jenster LM; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany., Diehl S; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany., Binder SC; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany., Normann S; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany., Mayr J; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany., Pritzl S; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany., Hagelauer E; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany., Kopp A; Institute of Structural Biology, Medical Faculty, University of Bonn, Bonn, Germany.; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia., Alon A; Whitehead Institute for Biomedical Research, Cambridge, MA, USA., Geyer M; Institute of Structural Biology, Medical Faculty, University of Bonn, Bonn, Germany., Ploegh HL; Whitehead Institute for Biomedical Research, Cambridge, MA, USA., Schmidt FI; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany. fschmidt@uni-bonn.de.; Whitehead Institute for Biomedical Research, Cambridge, MA, USA. fschmidt@uni-bonn.de.; Core Facility Nanobodies, Medical Faculty, University of Bonn, Bonn, Germany. fschmidt@uni-bonn.de.
المصدر: Nature communications [Nat Commun] 2024 Sep 26; Vol. 15 (1), pp. 8266. Date of Electronic Publication: 2024 Sep 26.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Single-Domain Antibodies*/metabolism , Single-Domain Antibodies*/chemistry , Inflammasomes*/metabolism , Phosphate-Binding Proteins*/metabolism , Pyroptosis*/drug effects , Intracellular Signaling Peptides and Proteins*/metabolism, Humans ; Animals ; HEK293 Cells ; Caspase 1/metabolism ; Caspase 3/metabolism ; Cell Membrane/metabolism ; Protein Multimerization ; Apoptosis/drug effects ; Gasdermins
مستخلص: Inflammasome activation results in the cleavage of gasdermin D (GSDMD) by pro-inflammatory caspases. The N-terminal domains (GSDMD NT ) oligomerize and assemble pores penetrating the target membrane. As methods to study pore formation in living cells are insufficient, the order of conformational changes, oligomerization, and membrane insertion remained unclear. We have raised nanobodies (VHHs) against human GSDMD and find that cytosolic expression of VHH GSDMD-1 and VHH GSDMD-2 prevents oligomerization of GSDMD NT and pyroptosis. The nanobody-stabilized GSDMD NT monomers partition into the plasma membrane, suggesting that membrane insertion precedes oligomerization. Inhibition of GSDMD pore formation switches cell death from pyroptosis to apoptosis, likely driven by the enhanced caspase-1 activity required to activate caspase-3. Recombinant antagonistic nanobodies added to the extracellular space prevent pyroptosis and exhibit unexpected therapeutic potential. They may thus be suitable to treat the ever-growing list of diseases caused by activation of (non-) canonical inflammasomes.
(© 2024. The Author(s).)
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معلومات مُعتمدة: SFB1403- 414786233 Deutsche Forschungsgemeinschaft (German Research Foundation); Germany's Excellence Strategy - EXC2151-390873048 Deutsche Forschungsgemeinschaft (German Research Foundation); GRK2168-272482170 Deutsche Forschungsgemeinschaft (German Research Foundation)
المشرفين على المادة: 0 (Single-Domain Antibodies)
0 (GSDMD protein, human)
0 (Inflammasomes)
0 (Phosphate-Binding Proteins)
0 (Intracellular Signaling Peptides and Proteins)
EC 3.4.22.36 (Caspase 1)
EC 3.4.22.- (Caspase 3)
0 (Gasdermins)
تواريخ الأحداث: Date Created: 20240926 Date Completed: 20240926 Latest Revision: 20240928
رمز التحديث: 20240928
DOI: 10.1038/s41467-024-52110-1
PMID: 39327452
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-024-52110-1