MYD88 L265P elicits mutation-specific ubiquitination to drive NF-κB activation and lymphomagenesis

• Published in: Blood 2021-03, Vol.137 (12), p.1615-1627
• Main Authors: Yu, Xinfang, Li, Wei, Deng, Qipan, Liu, Haidan, Wang, Xu, Hu, Hui, Cao, Ya, Xu-Monette, Zijun Y., Li, Ling, Zhang, Mingzhi, Lu, Zhongxin, Young, Ken H., Li, Yong
• Format: Article
• Language: English
• Subjects: Carcinogenesis - genetics; Cell Line, Tumor; HEK293 Cells; Humans; Lymphoid Neoplasia; Lymphoma - genetics; Mutation; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; NF-kappa B - metabolism; Ubiquitination
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2020004918

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-κB (NF-κB). MYD88L265P (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 MYD88L265P, resulting in enhanced recruitment of interleukin-1 receptor–associated kinases and elevated NF-κB activation. However, RNF138 had little effect on wild-type MYD88 (MYD88WT). With either RNF138 knockdown or mutation on MYD88 ubiquitination sites, MYD88L265P did not constitutively activate NF-κB. A20, a negative regulator of NF-κB signaling, mediated K48-linked polyubiquitination of RNF138 for proteasomal degradation. Depletion of A20 further augmented MYD88L265P-mediated NF-κB activation and lymphoma growth. Furthermore, A20 expression correlated negatively with RNF138 expression and NF-κB activation in lymphomas with MYD88L265P and in those without. Strikingly, RNF138 expression correlated positively with NF-κB activation in lymphomas with MYD88L265P, 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 MYD88L265P, while sparing MYD88WT, which is critical to innate immunity. •RNF138 catalyzes ubiquitination in MYD88L265P but not in wild-type MYD88.•A20 suppresses RNF138 expression to inhibit the oncogenic activity of MYD88L265P. [Display omitted]