Recurrent oncogenic mutations of MyD88 have been identified in a variety of lymphoid malignancies. Gain-of-function mutations of MyD88 constitutively activate downstream NF-κB signaling pathways, resulting in increased cellular proliferation and survival. However, whether MyD88 activity can be aberrantly regulated in MyD88-wild-type lymphoid malignancies remains poorly understood. SPOP is an adaptor protein of CUL3-based E3 ubiquitin ligase complex and frequently mutated genes in prostate and endometrial cancers. In this study, we reveal that SPOP binds to and induces the nondegradative ubiquitination of MyD88 by recognizing an atypical SPOP-binding motif in MyD88. This modification blocks Myddosome assembly and downstream NF-κB activation. SPOP is mutated in a subset of lymphoid malignancies, including diffuse large B-cell lymphoma (DLBCL). Lymphoid malignancies-associated SPOP mutants exhibited impaired binding to MyD88 and suppression of NF-κB activation. The DLBCL-associated, SPOP-binding defective mutants of MyD88 escaped from SPOP-mediated ubiquitination, and their effect on NF-κB activation is stronger than that of wild-type MyD88. Moreover, SPOP suppresses DLBCL cell growth in vitro and tumor xenograft in vivo by inhibiting the MyD88/NF-κB signaling. Therefore, SPOP acts as a tumor suppressor in DLBCL. Mutations in the SPOP–MyD88 binding interface may disrupt the SPOP–MyD88 regulatory axis and promote aberrant MyD88/NF-κB activation and cell growth in DLCBL.
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This work was supported by the National Natural Science Foundation of China (81972396, 81672558, and 81201533 to CW; 81572768 to XJ; 31400753, 81872109 to KG; 81572768, 81872260 to PZ), the Natural Science Foundation of Zhejiang Province (LY20C070001 to XJ), the Natural Science Foundation of Ningbo (2018A610213 to XJ), the National Undergraduate Training Program for Innovation and Entrepreneurship (201811646022 to LZ), the Student Research and Innovation Program of Ningbo University (2018SRIP1925 to QL) and the KC Wong Magna Fund in Ningbo University.
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Jin, X., Shi, Q., Li, Q. et al. CRL3–SPOP ubiquitin ligase complex suppresses the growth of diffuse large B-cell lymphoma by negatively regulating the MyD88/NF-κB signaling. Leukemia (2019) doi:10.1038/s41375-019-0661-z