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The RNA Surveillance Factor UPF1 Represses Myogenesis via Its E3 Ubiquitin Ligase Activity.

ABSTRACT: UPF1 is an RNA helicase that orchestrates nonsense-mediated decay and other RNA surveillance pathways. While UPF1 is best known for its basal cytoprotective role in degrading aberrant RNAs, UPF1 also degrades specific, normally occurring mRNAs to regulate diverse cellular processes. Here we describe a role for UPF1 in regulated protein decay, wherein UPF1 acts as an E3 ubiquitin ligase to repress human skeletal muscle differentiation. Suppressing UPF1 accelerates myogenesis, while ectopically increasing UPF1 levels slows myogenesis. UPF1 promotes the decay of MYOD protein, a transcription factor that is a master regulator of myogenesis, while leaving MYOD mRNA stability unaffected. UPF1 acts as an E3 ligase via its RING domain to promote MYOD protein ubiquitination and degradation. Our data characterize a regulatory role for UPF1 in myogenesis, and they demonstrate that UPF1 provides a mechanistic link between the RNA and protein decay machineries in human cells.

SUBMITTER: Feng Q

PROVIDER: S-EPMC5536975 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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The RNA Surveillance Factor UPF1 Represses Myogenesis via Its E3 Ubiquitin Ligase Activity.

Feng Qing Q Jagannathan Sujatha S Bradley Robert K RK

Molecular cell 20170629 2

UPF1 is an RNA helicase that orchestrates nonsense-mediated decay and other RNA surveillance pathways. While UPF1 is best known for its basal cytoprotective role in degrading aberrant RNAs, UPF1 also degrades specific, normally occurring mRNAs to regulate diverse cellular processes. Here we describe a role for UPF1 in regulated protein decay, wherein UPF1 acts as an E3 ubiquitin ligase to repress human skeletal muscle differentiation. Suppressing UPF1 accelerates myogenesis, while ectopically in ...[more]

PMID: 28669802

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Project description:BackgroundDegrons are short linear motifs, bound by E3 ubiquitin ligase to target protein substrates to be degraded by the ubiquitin-proteasome system. Mutations leading to deregulation of degron functionality disrupt control of protein abundance due to mistargeting of proteins destined for degradation and often result in pathologies. Targeting degrons by small molecules also emerges as an exciting drug design strategy to upregulate the expression of specific proteins. Despite their essential function and disease targetability, reliable identification of degrons remains a conundrum. Here, we developed a deep learning-based model named Degpred that predicts general degrons directly from protein sequences.ResultsWe showed that the BERT-based model performed well in predicting degrons singly from protein sequences. Then, we used the deep learning model Degpred to predict degrons proteome-widely. Degpred successfully captured typical degron-related sequence properties and predicted degrons beyond those from motif-based methods which use a handful of E3 motifs to match possible degrons. Furthermore, we calculated E3 motifs using predicted degrons on the substrates in our collected E3-substrate interaction dataset and constructed a regulatory network of protein degradation by assigning predicted degrons to specific E3s with calculated motifs. Critically, we experimentally verified that a predicted SPOP binding degron on CBX6 prompts CBX6 degradation and mediates the interaction with SPOP. We also showed that the protein degradation regulatory system is important in tumorigenesis by surveying degron-related mutations in TCGA.ConclusionsDegpred provides an efficient tool to proteome-wide prediction of degrons and binding E3s singly from protein sequences. Degpred successfully captures typical degron-related sequence properties and predicts degrons beyond those from previously used motif-based methods, thus greatly expanding the degron landscape, which should advance the understanding of protein degradation, and allow exploration of uncharacterized alterations of proteins in diseases. To make it easier for readers to access collected and predicted datasets, we integrated these data into the website http://degron.phasep.pro/ .

Dataset Information

The RNA Surveillance Factor UPF1 Represses Myogenesis via Its E3 Ubiquitin Ligase Activity.

Publications

The RNA Surveillance Factor UPF1 Represses Myogenesis via Its E3 Ubiquitin Ligase Activity.

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