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Different polyubiquitin chain linkages direct substrates toward distinct cellular pathways. K63-linked ubiquitylation is known to regulate proteasome-independent events such as signal transduction, but its function in the context of heterogeneous ubiquitin chains remains unclear. Here, we report that K63 ubiquitylation plays a critical role in proteasome-mediated substrate degradation by serving as a "seed" for K48/K63 branched ubiquitin chains. Quantitative analysis revealed that K48/K63 branched linkages preferentially associate with proteasomes in cells. We found that ITCH-dependent K63 ubiquitylation of the proapoptotic regulator TXNIP triggered subsequent assembly of K48/K63 branched chains by recruiting ubiquitin-interacting ligases such as UBR5, leading to TXNIP degradation. These results reveal a role for K63 chains as a substrate-specific mark for proteasomal degradation involved in regulating cell fate. Our findings provide insight into how cellular interpretation of the ubiquitin code is altered by combinations of ubiquitin linkages.

K63 ubiquitylation triggers proteasomal degradation by seeding branched ubiquitin chains