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Title:Cleavage-mediated regulation of Myd88 signaling by inflammasome-activated caspase-1
Authors:ID Avbelj, Monika (Author)
ID Hafner Bratkovič, Iva (Author)
ID Lainšček, Duško (Author)
ID Manček Keber, Mateja (Author)
ID Peternelj, Tina Tinkara (Author)
ID Panter, Gabriela (Author)
ID Treon, Steven P. (Author)
ID Gole, Boris (Author)
ID Potočnik, Uroš (Author)
ID Jerala, Roman (Author)
Files:.pdf Cleavage-Mediated_Regulation_of_My-Avbelj-2022.pdf (12,17 MB)
MD5: 6E9A6C4480175499256BFD53187CEC8C
URL https://www.frontiersin.org/articles/10.3389/fimmu.2021.790258/full
Work type:Scientific work
Typology:1.01 - Original Scientific Article
Organization:MF - Faculty of Medicine
FKKT - Faculty of Chemistry and Chemical Engineering
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:Myeloid differentiation factor 88, Myd88, caspase-1, inflammasomes, regulation, innate immunity, inflammation
Publication status:Published
Publication version:Version of Record
Publication date:01.01.2022
Year of publishing:2022
Number of pages:str. 1-14
Numbering:Vol. 12
PID:20.500.12556/DKUM-85015 New window
ISSN on article:1664-3224
COBISS.SI-ID:93261315 New window
DOI:10.3389/fimmu.2021.790258 New window
Publication date in DKUM:16.08.2023
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Record is a part of a journal

Title:Frontiers in immunology
Shortened title:Front. immunol.
Publisher:Frontiers Research Foundation
COBISS.SI-ID:30774233 New window

Document is financed by a project

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:Z3-6786
Name:Aktivacija inflamasoma negativno povratno vpliva na signalne poti odvisne od MyD88

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:J3-6804
Name:Identifikacija novih genov, mikro RNA ter biomarkerjev naravne imunosti za hiperholesterolemijo

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:J3-1746
Name:Vloga celične smrti v različnih aktivacijskih poteh inflamasoma NLRP3 in njena uporaba za inovativno imunoterapijo raka

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:J3-9258
Name:Molekularno genetski biooznačevalci in mehanizmi neodzivnosti na biološko zdravljenje zanti-TNF bolnikov s kroničnimi imunskimi boleznimi

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:P4-0176
Name:Sintezna biologija in imunologija

Funder:Drugi - Drug financer ali več financerjev
Project number:ICGEB CRP SVN18-01
Name:Sonogenetics: ultrasound-inducible transcriptional regulation


License:CC BY 4.0, Creative Commons Attribution 4.0 International
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

Keywords:mieloidni diferenciacijski primarni odgovor 88, Myd88, kaspaza 1, prirojena imunost, vnetje


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