Kelch-Like Protein 6 Negatively Regulates NF-κB Activation in Lymphoma

Members of the kelch-like (KLHL) protein family act as substrate adaptors for cullin 3 (CUL3) ubiquitin ligases and are associated with both solid and hematologic cancers. Mutations in KLHL6 have been identified in B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL), but although KLHL6 has been implicated in B-cell receptor (BCR) signaling in B cells, the role of KLHL6 in DLBCL progression is unknown. To elucidate the role of KLHL6 mutations in DLBCL, Choi and colleagues evaluated the frequency of KLHL6 mutations in patients with B-cell malignancies and found that DLBCLs exhibited the highest frequency of KLHL6 mutations. Comparison of the protein interactomes of wild-type KLHL6 and a cancer-associated KLHL6 mutant (L65P) showed that wild-type, but not mutant, KLHL6 associated with CUL3 and assembled a complex with E3 ubiquitin ligase activity in vitro. Importantly, wild-type—but not mutant—KLHL6 induced the ubiquitylation and degradation of Roquin-2, an RNA-binding protein which promotes mRNA decay, in DLBCL in vitro. Loss of KLHL6 or expression of a nondegradable Roquin-2 mutant in DLBCL cells resulted in increased proliferation and decreased apoptosis in vitro, and loss of KLHL6 or mutant KLHL6 promoted tumor growth in vivo compared with wild-type KLHL6; further, ablation of Roquin-2 reduced the growth of KLHL6-null DLBCL cells. Moreover, BCR signaling induced Roquin-2 degradation in a KLHL6-dependent manner to inhibit Roquin-2–mediated downregulation of the expression of BCR target genes such as TNFAIP3, a negative regulator of NF-kB. Together, these results describe the tumor suppressor function of KLHL6 in DLBCL and elucidate the mRNA decay–dependent mechanism by which BCR signaling drives DLBCL proliferation.

Choi J, Lee K, Ingvarsdottir K, Bonasio R, Saraf A, Florens L, Washburn MP, et al. Loss of KLHL6 promotes diffuse large B-cell lymphoma growth and survival by stabilizing the mRNA decay factor roquin2. Nature Cell Biol 2018;20:586–96.

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