MyD88, the key adaptor of most TLR, IL-1R and IL-18R signaling, has been implicated in development of several inflammatory diseases, including lymphoma. Genomic studies of B-cell malignancies samples revealed several mutations in the core of MyD88 TIR domain that trigger constitutive activation of proinflammatory signaling serving as the survival signal for cancer cells. Our study aimed to elucidate the molecular mechanism underlying activation of MyD88. In contrast to the wild type TIR domain of MyD88, which inhibits MyD88-mediated activation, results from luciferase and LUMIER assays showed that TIR domain of lymphoma-associated MyD88 mutants triggers cell activation dependent on the endogenous wt MyD88, similar as observed previously for tethered TIR domains of MyD88. The TIR domain of mutants interacts with wild-type MyD88 explaining why heterozygous mutation could be sufficient as a driver mutation in lymphoma development. Mutated TIR domains displayed an intrinsic propensity for augmented oligomerization and spontaneous formation of cytosolic Myddosome aggregates in lymphoma cell lines assessed by confocal microscopy and immunoblots. Using inhibitory peptides blocking of MyD88 oligomerization significantly reduced TIR-TIR oligomerization and induced apoptosis in DLBCL cell lines in a mutation-dependent fashion. Besides experimental approaches in cellular model systems and in lymphoma cell lines, we also employed molecular dynamics simulations. Analysis of additional designed mutations supports our findings that constitutive activity is caused by allosteric oligomerization. We showed that hyperactive phenotype of lymphoma-associated mutations is caused by increased oligomerization propensity of the MyD88 TIR domain. Our data are important for understanding the MyD88-driven oncogenesis and bear significant therapeutic implications.
B.03 Paper at an international scientific conference
COBISS.SI-ID: 5794074