Intrinsic signaling pathways modulate targeted protein degradation Article Swipe
Mori Yuki
,
Yoshino Akizuki
,
Rikuto Honda
,
Miyu Takao
,
Ayaka Tsuchimoto
,
Sota Hashimoto
,
H. Iio
,
Masakazu Kato
,
Ai Kaiho-Soma
,
Yasushi Saeki
,
Jun Hamazaki
,
Shigeo Murata
,
Toshikazu Ushijima
,
Naoko Hattori
,
Fumiaki Ohtake
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1038/s41467-024-49519-z
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1038/s41467-024-49519-z
Targeted protein degradation is a groundbreaking modality in drug discovery; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the anticancer target BRD4 and related neosubstrates BRD2/3 and CDK9 induced by CRL2 VHL - or CRL4 CRBN -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and formation of the BRD4–PROTAC–CRL2 VHL ternary complex; by contrast, HSP90 inhibition promotes BRD4 degradation after the ubiquitylation step. Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1038/s41467-024-49519-z
- https://www.nature.com/articles/s41467-024-49519-z.pdf
- OA Status
- gold
- Cited By
- 13
- References
- 40
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4400248672
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Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4400248672Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1038/s41467-024-49519-zDigital Object Identifier
- Title
-
Intrinsic signaling pathways modulate targeted protein degradationWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2024Year of publication
- Publication date
-
2024-07-02Full publication date if available
- Authors
-
Mori Yuki, Yoshino Akizuki, Rikuto Honda, Miyu Takao, Ayaka Tsuchimoto, Sota Hashimoto, H. Iio, Masakazu Kato, Ai Kaiho-Soma, Yasushi Saeki, Jun Hamazaki, Shigeo Murata, Toshikazu Ushijima, Naoko Hattori, Fumiaki OhtakeList of authors in order
- Landing page
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https://doi.org/10.1038/s41467-024-49519-zPublisher landing page
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https://www.nature.com/articles/s41467-024-49519-z.pdfDirect link to full text PDF
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YesWhether a free full text is available
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goldOpen access status per OpenAlex
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https://www.nature.com/articles/s41467-024-49519-z.pdfDirect OA link when available
- Concepts
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Cell biology, Ubiquitin, BRD4, Protein degradation, Signal transduction, Chromatin, Chemistry, Proteasome, Biology, Biochemistry, Histone, Bromodomain, DNA, GeneTop concepts (fields/topics) attached by OpenAlex
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13Total citation count in OpenAlex
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2025: 11, 2024: 2Per-year citation counts (last 5 years)
- References (count)
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40Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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