Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 7, Pages E1401-E1408Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1716673115
Keywords
ubiquitin; proteasome; K63-linked ubiquitin chain; ITCH; NEDD4 family E3 ligase
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Funding
- Japan Ministry of Education, Culture, Sports, Science, and Technology/Japan Society for the Promotion of Science KAKENHI [JP24112004, JP17H03986, JP16K14702, JP24112005, JP26000014]
- Grants-in-Aid for Scientific Research [26293018, 26000014, 16K14702, 17H03986] Funding Source: KAKEN
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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.
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