Monika Avbelj (Author), Iva Hafner Bratkovič (Author), Duško Lainšček (Author), Mateja Manček Keber (Author), Tina Tinkara Peternelj (Author), Gabriela Panter (Author), Steven P. Treon (Author), Boris Gole (Author), Uroš Potočnik (Author), Roman Jerala (Author)

Abstract

Coordination among multiple signaling pathways ensures an appropriate immune response, where a signaling pathway may impair or augment another signaling pathway. Here, we report a negative feedback regulation of signaling through the key innate immune mediator MyD88 by inflammasome-activated caspase-1. NLRP3 inflammasome activation impaired agonist- or infection-induced TLR signaling and cytokine production through the proteolytic cleavage of MyD88 by caspase-1. Site-specific mutagenesis was used to identify caspase-1 cleavage site within MyD88 intermediary segment. Different cleavage site location within MyD88 defined the functional consequences of MyD88 cleavage between mouse and human cells. LPS/monosodium urate–induced mouse inflammation model corroborated the physiological role of this mechanism of regulation, that could be reversed by chemical inhibition of NLRP3. While Toll/interleukin-1 receptor (TIR) domain released by MyD88 cleavage additionally contributed to the inhibition of signaling, Waldenström’s macroglobulinemia associated MyD88L265P mutation is able to evade the caspase-1-mediated inhibition of MyD88 signaling through the ability of its TIRL265P domain to recruit full length MyD88 and facilitate signaling. The characterization of this mechanism reveals an additional layer of innate immunity regulation.

Keywords

regulation;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: KI - National Institute of Chemistry
UDC: 616-097
COBISS: 93261315 Link will open in a new window
ISSN: 1664-3224
Views: 8
Downloads: 1
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Other data

Secondary language: Slovenian
Secondary keywords: Inflammation;Immunity, innate;Inflammasomes;Caspase 1;Myeloid differentiation factor 88;
Type (COBISS): Scientific work
Pages: str. 1-14
Issue: ǂVol. ǂ12
Chronology: Jan. 2022
DOI: 10.3389/fimmu.2021.790258
ID: 19810164