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| Status |
Public on Jun 06, 2024 |
| Title |
Act1 modulates mRNA metabolism upon IL-17 stimulation |
| Organism |
Mus musculus |
| Experiment type |
Other
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| Summary |
The IL-17 receptor adaptor molecule Act1, an RNA binding protein, plays a critical role in IL-17-mediated cancer progression. Here we report a novel mechanism for how IL-17/Act1 induces chemoresistance by modulating redox homeostasis through epitranscriptomic regulation of antioxidant RNA metabolism. Transcriptome-wide mapping of direct Act1-RNA interactions revealed that Act1 binds to the 5'UTR of antioxidant mRNAs and Wilms' tumor 1-associating protein (WTAP), a key regulator in m6A methyltransferase complex. Strikingly, Act1's binding sites are located in proximity to m6A modification sites, which allows Act1 to promote the recruitment of elF3G for cap-independent translation. Loss of Act1’s RNA binding activity or Wtap knockdown abolished IL-17-induced m6A modification and translation of Wtap and antioxidant mRNAs, indicating a feedforward mechanism of Act1-WTAP loop. We then developed antisense oligonucleotides (Wtap ASO) that specifically disrupts Act1’s binding to Wtap mRNA, abolishing IL-17/Act1-WTAP-mediated antioxidant protein production during chemotherapy. Wtap ASO substantially increased the antitumor efficacy of cisplatin, demonstrating a potential therapeutic strategy for chemoresistance.
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| Overall design |
Cross-Linking and Immunoprecipitation in combination with next-generation sequencing (CLIP-seq) was performed to identify Act1-binding sites at high resolution in a transcriptome-wide manner.
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| Contributor(s) |
Hong L |
| Citation missing |
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| |
| Submission date |
Apr 12, 2024 |
| Last update date |
Jun 07, 2024 |
| Contact name |
Lingzi Hong |
| E-mail(s) |
lxh291@case.edu
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| Organization name |
Case western reserve university
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| Department |
biochemistry
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| Street address |
10900 Euclid Avenue
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| City |
cleveland |
| State/province |
oh |
| ZIP/Postal code |
44106 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (3) |
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| Relations |
| BioProject |
PRJNA1099569 |
