Evidence map›Paper›PMID 40128189›Full record

ArticleNature communications2025

Combinatorial ubiquitin code degrades deubiquitylation-protected substrates.

Mai Morita, Miyu Takao, Honoka Tokuhisa, Ryotaro Chiba, Shota Tomomatsu, Yoshino Akizuki, Takuya Tomita, Akinori Endo, Yasushi Saeki, Yusuke Sato and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

9 citing papers in PubMed.

  1. Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Mai MoritaLaboratory of Protein Degradation, Institute for Advanced Life Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan.
Miyu TakaoLaboratory of Protein Degradation, Institute for Advanced Life Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan.
Honoka TokuhisaDepartment of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-cho Minami, Tottori-shi, Tottori, Japan.ORCID http://orcid.org/0009-0004-1085-5018
Ryotaro ChibaLaboratory of Protein Degradation, Institute for Advanced Life Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan.
Shota TomomatsuLaboratory of Protein Degradation, Institute for Advanced Life Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan.
Yoshino AkizukiLaboratory of Protein Degradation, Institute for Advanced Life Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan.
Takuya TomitaDivision of Protein Metabolism, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, Japan.ORCID http://orcid.org/0000-0003-4568-9940
Akinori EndoProtein Metabolism Project, Tokyo Metropolitan Institute of Medical Sciences, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, Japan.
Yasushi SaekiDivision of Protein Metabolism, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, Japan.ORCID http://orcid.org/0000-0002-9202-5453
Yusuke SatoDepartment of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-cho Minami, Tottori-shi, Tottori, Japan.
Fumiaki OhtakeLaboratory of Protein Degradation, Institute for Advanced Life Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan. f-ohtake@hoshi.ac.jp.ORCID http://orcid.org/0000-0002-8590-6172

Funding

Japan Agency for Medical Research and Development (AMED) 24gm1410007h0004MEXT | Japan Society for the Promotion of Science (JSPS) JP21H02433MEXT | Japan Society for the Promotion of Science (JSPS) JP23H04922
6 · The paper itself

Abstract

Protein ubiquitylation is maintained by a dynamic balance of the conjugation and deconjugation of ubiquitin. It remains unclear how deubiquitylation-stabilized substrates are directed for degradation. Branched ubiquitin chains promote substrate degradation through the proteasome. TRIP12 and UBR5 are HECT-type E3 ubiquitin ligases, which are specific for lysine 29 (K29) and lysine 48 (K48) linkages, respectively. Here, we show that the deubiquitylase (DUB) OTUD5 is cooperatively modified by TRIP12 and UBR5, resulting in conjugation of K29/K48 branched ubiquitin chains and accelerated proteasomal degradation. TRIP12-OTUD5 antagonism regulates TNF-α-induced NF-κB signaling. Mechanistically, OTUD5 readily cleaves K48 linkages, but does not affect K29 linkages. Consequently, K29 linkages overcome OTUD5 DUB activity to facilitate UBR5-dependent K48-linked chain branching. This mechanism is applicable to other OTUD5-associated TRIP12 substrates. Thus, the combination of DUB-resistant and proteasome-targeting ubiquitin linkages promotes the degradation of deubiquitylation-protected substrates, underscoring the role of branched ubiquitin chains in shifting the ubiquitin conjugation/deconjugation equilibrium.

Indexed as

EndopeptidasesUbiquitinUbiquitin-Protein LigasesAdaptor Proteins, Signal TransducingCarrier ProteinsHEK293 CellsHumansLysineNF-kappa BProteasome Endopeptidase ComplexProteolysisSignal TransductionSubstrate SpecificityTumor Necrosis Factor-alphaUbiquitinationAdaptor Proteins, Signal TransducingCarrier ProteinsEndopeptidasesLysineNF-kappa BProteasome Endopeptidase ComplexTRIP12 protein, humanTumor Necrosis Factor-alphaUbiquitinUbiquitin-Protein LigasesUBR5 protein, human

Identifiers

PMID40128189
PMCPMC11933340

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Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.