Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line, Tumor
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Cell Proliferation*
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Cell Survival
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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HEK293 Cells
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Humans
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Lymphoma, Large B-Cell, Diffuse / enzymology*
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Lymphoma, Large B-Cell, Diffuse / genetics
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Lymphoma, Large B-Cell, Diffuse / pathology
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Mice, Inbred NOD
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Mice, SCID
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Mutation
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NF-kappa B / metabolism
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Protein Stability
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Proteolysis
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RNA Stability*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism*
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Receptors, Antigen, B-Cell / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction
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Tumor Necrosis Factor alpha-Induced Protein 3 / genetics
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Tumor Necrosis Factor alpha-Induced Protein 3 / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Tyrosine
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Ubiquitination
Substances
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Carrier Proteins
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KLHL6 protein, human
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NF-kappa B
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RC3H2 protein, human
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RNA, Messenger
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Receptors, Antigen, B-Cell
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Repressor Proteins
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Tumor Suppressor Proteins
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Tyrosine
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TNFAIP3 protein, human
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Tumor Necrosis Factor alpha-Induced Protein 3