Journal
MOLECULAR CELL
Volume 67, Issue 3, Pages 423-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2017.06.021
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Funding
- Max Planck Society
- Deutsche Forschungsgemeinschaft [SFB 646 B4, PF 794/1-1, PF 794/3-1, SFB 1064 A23]
- Center for Integrated Protein Science Munich
- Louis-Jeantet Foundation
- ERC Advanced Grant [ERC-2013-AdG-339176]
- Deutsche Forschungsgemeinschaft
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Accurate pre-mRNA splicing is needed for correct gene expression and relies on faithful splice site recognition. Here, we show that the ubiquitin-like protein Hub1 binds to the DEAD-box helicase Prp5, a key regulator of early spliceosome assembly, and stimulates its ATPase activity thereby enhancing splicing and relaxing fidelity. High Hub1 levels enhance splicing efficiency but also cause missplicing by tolerating suboptimal splice sites and branchpoint sequences. Notably, Prp5 itself is regulated by a Hub1-dependent negative feedback loop. Since Hub1-mediated splicing activation induces cryptic splicing of Prp5, it also represses Prp5 protein levels and thus curbs excessive missplicing. Our findings indicate that Hub1 mediates enhanced, but error-prone splicing, a mechanism that is tightly controlled by a feedback loop of PRP5 cryptic splicing activation.
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