AA28-67 domain within MyD88 suppresses c-myc activity and expression to regulate differentiation and function of dendritic cells.

The mechanism by which c-myc expression in undifferentiated cells rapidly declines following induction of differentiation is poorly characterized. We demonstrate here that MyD88, which can activate NF-κB and MAPK, also suppresses c-myc activity and expression. The aa 28–67 domain, a highly conserved region within MyD88, plays a critical role in the MyD88-mediated inhibition. Indeed, deletion of the aa 28–67 domain (MyD88Δ28–67) or mutation of the highly conserved amino acid residue phenylalanine (aa 36) to aspartic acid (MyD88ΔF36D) significantly promoted c-myc activity and expression. Additionally, we found that MyD88Δ28–67-mediated c-myc activity and expression could be abrogated using PI3K inhibitor, suggesting that the PI3K/Akt signaling pathway may be involved in MyD88-mediated suppression of c-myc. Compared to MyD88-transduced DCs, MyD88Δ28–67- and MyD88ΔF36D-transduced DCs derived from MyD88−/− bone marrow cells had lower antigen-presenting ability. Thus, MyD88 induces the differentiation and maturation of DCs not only by activating NF-κB and MAPK but also via suppressing c-myc activity and expression.