Myd88 L265p Elicits Mutation-Specific Ubiquitination To Drive Nf-Kappa B Activation And Lymphomagenesis

Myeloid differentiation primary response protein 88 (MYD88) is a critical universal adapter that transduces signaling from Toll-like and interleukin receptors to downstream nuclear factor-kappa B (NF-kappa B). MYD88(L265P) (leucine changed to proline at position 265) is a gain-of-function mutation that occurs frequently in B-cell malignancies such as Waldenstrom macroglobulinemia. In this study, E3 ligase RING finger protein family 138 (RNF138) catalyzed K63-linked nonproteolytic polyubiquitination of MYD88(L265P), resulting in enhanced recruitment of interleukin-1 receptor-associated kinases and elevated NF-kappa B activation. However, RNF138 had little effect on wild-type MYD88 (MYD88(WT)). With either RNF138 knockdown or mutation on MYD88 ubiquitination sites, MYD88(L265P) did not constitutively activate NF-kappa B. A20, a negative regulator of NF-kappa B signaling, mediated K48-linked polyubiquitination of RNF138 for proteasomal degradation. Depletion of A20 further augmented MYD88(L265P)-mediated NF-kappa B activation and lymphoma growth. Furthermore, A20 expression correlated negatively with RNF138 expression and NF-kappa B activation in lymphomas with MYD88(L265P) and in those without. Strikingly, RNF138 expression correlated positively with NF-kappa B activation in lymphomas with MYD88(L265P), but not in those without it. Our study revealed a novel mutation-specific biochemical reaction that drives B-cell oncogenesis, providing a therapeutic opportunity for targeting oncogenic MYD88(L265P), while sparing MYD88(WT), which is critical to innate immunity.