20.500.12556/DKUM-85015 Cleavage-mediated regulation of Myd88 signaling by inflammasome-activated caspase-1 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. Myeloid differentiation factor 88 Myd88 caspase-1 inflammasomes regulation innate immunity inflammation mieloidni diferenciacijski primarni odgovor 88 Myd88 kaspaza 1 prirojena imunost vnetje true false true Angleški jezik Slovenski jezik Znanstveno delo 2023-08-16 10:01:33 2023-08-16 10:01:33 2023-08-17 03:08:54 0000-00-00 00:00:00 2022 0 0 str. 1-14 Vol. 12 Jan. 2022 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 2022-01-01 616-097 93261315 10.3389/fimmu.2021.790258 1664-3224 Cleavage-Mediated_Regulation_of_My-Avbelj-2022.pdf Cleavage-Mediated_Regulation_of_My-Avbelj-2022.pdf 1 6E9A6C4480175499256BFD53187CEC8C 28b93c23d63b9f6ecbf5bb664079244900a580d8ca5c931e90bcd15d2d36572c b0501340-3c0d-11ee-b5e9-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=169545 https://www.frontiersin.org/articles/10.3389/fimmu.2021.790258/full 1 1fe39df0-3c0b-11ee-b5e9-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=169543 Medicinska fakulteta Fakulteta za kemijo in kemijsko tehnologijo 0 0 0