Loss of KLHL6 promotes diffuse large B-cell lymphoma growth and survival by stabilizing the mRNA decay factor roquin2

• Published in: Nature cell biology Vol. 20; no. 5; pp. 586 - 596
• Main Authors: Choi, Jaewoo, Lee, Kyutae, Ingvarsdottir, Kristin, Bonasio, Roberto, Saraf, Anita, Florens, Laurence, Washburn, Michael P, Tadros, Saber, Green, Michael R, Busino, Luca
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.05.2018
• Subjects: Analysis; Animals; B-cell lymphoma; B-cell receptor; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell activation; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cullin; Decay; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gene mutation; Growth; HEK293 Cells; Humans; Ligases; Lymphocytes B; Lymphoma; Lymphoma, Large B-Cell, Diffuse - enzymology; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - pathology; Lymphomas; Messenger RNA; Mice, Inbred NOD; Mice, SCID; mRNA turnover; Mutation; Necrosis; NF-kappa B - metabolism; NF-κB protein; Protein Stability; Proteolysis; Receptor mechanisms; Receptors, Antigen, B-Cell - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Ribonucleic acid; RNA; RNA Stability; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Substrates; Survival; Tumor necrosis factor; Tumor Necrosis Factor alpha-Induced Protein 3 - genetics; Tumor Necrosis Factor alpha-Induced Protein 3 - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; Tyrosine; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; Xenografts; Xenotransplantation
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-018-0084-5

Kelch-like protein 6 (KLHL6) is an uncharacterized gene mutated in diffuse large B-cell lymphoma (DLBCL). Here we report that KLHL6 assembles with cullin3 to form a functional cullin-RING ubiquitin ligase. Mutations in KLHL6 inhibit its ligase activity by disrupting the interaction with cullin3. Loss of KLHL6 favours DLBCL growth and survival both in vitro and in xenograft models. We further established that the mRNA decay factor roquin2 is a substrate of KLHL6. Degradation of roquin2 is dependent on B-cell receptor activation, and requires the integrity of the Tyr691 residue in roquin2 that is essential for its interaction with KLHL6. A non-degradable roquin2(Y691F) mutant requires its RNA-binding ability to phenocopy the effect of KLHL6 loss. Stabilization of roquin2 promotes mRNA decay of the tumour suppressor and NF-κB pathway inhibitor, tumour necrosis factor-α-inducible gene 3. Collectively, our findings uncover the tumour suppressing mechanism of KLHL6.