Loss of KLHL6 promotes diffuse large B-cell lymphoma growth and survival by stabilizing the mRNA decay factor Roquin2

Kelch-like protein 6 (KLHL6) is an uncharacterized gene mutated in diffuse large B-cell lymphoma (DLBCL). We report that KLHL6 assembles with CULLIN3 to form a functional CULLIN-Ring ubiquitin ligase. Mutations of KLHL6 inhibit its ligase activity by disrupting the interaction with CULLIN3. Loss of KLHL6 favors DLBCL growth and survival both in vitro and in xenograft models. We further established the mRNA decay factor Roquin2 as a substrate of KLHL6. Degradation of Roquin2 is dependent on B-cell receptor activation, and requires the integrity of the tyrosine 691 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 tumor suppressor and NF-κB pathway inhibitor, tumor necrosis factor-α-inducible gene 3 (TNFAIP3). Collectively, our findings uncover the tumor suppressing mechanism of KLHL6.