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

Povzetek

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.

Ključne besede

regulation;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: KI - Kemijski inštitut
UDK: 616-097
COBISS: 93261315 Povezava se bo odprla v novem oknu
ISSN: 1664-3224
Št. ogledov: 8
Št. prenosov: 1
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: Inflammation;Immunity, innate;Inflammasomes;Caspase 1;Myeloid differentiation factor 88;
Vrsta dela (COBISS): Znanstveno delo
Strani: str. 1-14
Zvezek: ǂVol. ǂ12
Čas izdaje: Jan. 2022
DOI: 10.3389/fimmu.2021.790258
ID: 19810164