MyD88 protein destabilization mitigates NF-κB-dependent protection against macrophage apoptosisLainšček, Duško (Avtor) Horvat, Simon (Avtor) Dolinar, Klemen (Avtor) Ivanovski, Filip (Avtor) Romih, Rok (Avtor) Pirkmajer, Sergej (Avtor) Jerala, Roman (Avtor) Manček Keber, Mateja (Avtor) MyD88NF-κB signalingapoptosishomeostasisoxidative stressVarious signaling pathways are essential for both the innate immune response and the maintenance of cell homeostasis, requiring coordinated interactions among them. In this study, a mutation in the caspase-1 recognition site within MyD88 abolished inflammasome-dependent negative regulation, causing phenotypic changes in mice with some similarities to human NEMO-deficiencies. The MyD88$^{D162E}$ mutation reduced MyD88 protein levels and colon inflammation in DSS-induced colitis mice but did not affect cytokine expression in bone marrow-derived macrophages (BMDMs). However, compared to MyD88$^{wt}$ counterparts, MyD88$^{D162E}$ BMDMs had increased oxidative stress and dysfunctional mitochondria, along with reduced prosurvival Bcl-xL and BTK expression, rendering cells more prone to apoptosis, exacerbated by ibrutinib treatment. NF-κB activation by lipopolysaccharide mitigated this sensitive phenotype. These findings underscore the importance of MyD88$^{wt}$ signaling for NF-κB activation, protecting against macrophage premature apoptosis at resting state. Targeting MyD88 quantity rather than just its signaling could be a promising strategy for MyD88-driven lymphoma treatment.20242024-12-05 04:02:01Članek v reviji165389sl