The Upf Factor Complex Interacts with Aberrant Products Derived from mRNAs Containing a Premature Termination Codon and Facilitates Their Proteasomal Degradation

Kuroha, Kazushige; Ando, Koji; Nakagawa, Reiko; Inada, Toshifumi

doi:10.1074/jbc.m113.460691

Cited by 26 publications

(39 citation statements)

References 36 publications

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“…Notably, we also demonstrated that truncated SERPINB7 protein from the mutant r.796c>u transcripts is degraded by the 26S proteasome. In yeast, mRNAs harboring a faux 3 0 UTR stimulate Upf1-dependent proteasome-mediated degradation of the PTC products (Kuroha et al, 2009;Kuroha et al, 2013;Sugiyama et al, 2017). These findings collectively indicate that mRNA and protein stability might be regulated by the aberrantly long 3 0 UTR of mutant transcripts in humans.…”

Section: Discussionmentioning

confidence: 85%

Gentamicin-Induced Readthrough and Nonsense-Mediated mRNA Decay of SERPINB7 Nonsense Mutant Transcripts

Ohguchi

Nomura

Suzuki

et al. 2018

Journal of Investigative Dermatology

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Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive skin disorder with a high, unmet medical need that is caused by mutations in SERPINB7. Almost all NPPK patients carry the founder nonsense mutation c.796C>T (p.Arg266Ter) in the last exon of SERPINB7. Here we sought to determine whether topical nonsense-suppression (readthrough) therapy using gentamicin is applicable to NPPK. First, we demonstrated that gentamicin enhanced readthrough activity in cells transfected with SERPINB7 cDNA carrying the mutation and promoted full-length SERPINB7 protein synthesis in NPPK keratinocytes. We next conducted an investigator-blinded, randomized, bilaterally controlled compassionate use study of topical gentamicin in which five NPPK patients with c.796C>T were enrolled. Patients' self-reported improvement of hyperkeratosis was significantly greater on the gentamicin side than the control side (P = 0.0349). In two patients, hyperkeratosis was improved on the gentamicin side, as determined by a blinded-investigator assessment. These results indicate the therapeutic potential of topical gentamicin for NPPK. Unexpectedly, we also found that mutant SERPINB7 mRNAs harboring r.796c>u were degraded by nonsense-mediated mRNA decay. Furthermore, the truncated SERPINB7 protein was degraded via a proteasome-mediated pathway. These findings provide important insights into the mRNA/protein quality-control system in humans, which could be a potential therapeutic target for genetic diseases.

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Section: Discussionmentioning

confidence: 85%

Gentamicin-Induced Readthrough and Nonsense-Mediated mRNA Decay of SERPINB7 Nonsense Mutant Transcripts

Ohguchi

Nomura

Suzuki

et al. 2018

Journal of Investigative Dermatology

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“…For example, UPF1’s E3 activity may contribute to the degradation of abnormal and potentially deleterious peptides encoded by NMD substrates. Previous studies in yeast found that peptides encoded by reporter NMD substrates were degraded by the proteasome, and that Upf1 was important for this process (Kuroha et al, 2013; 2009; Verma et al, 2013). However, the method by which Upf1 promoted selective degradation of such peptides was not identified.…”

Section: Discussionmentioning

confidence: 99%

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

2017

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SUMMARY 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 demonstrate that UPF1 provides a mechanistic link between the RNA and protein decay machineries in human cells.

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“…Some encode full-length proteins while others have truncated ORFs 49, 78,86 . Structural and biochemical evidence suggest that UPF1 has ubiquitin-ligase activity 99,100 , which may stimulate the proteasome to degrade aberrant proteins encoded by PTC-containing mRNAs 101,102 . The data supporting such NMD-associated protein degradation is limited to a few model substrates in S. cerevisiae and it appears that UPF1-stimulated acceleration of degradation only occurs for proteins that are inherently unstable 101,102 .…”

Section: Effects Of Nmd On Gene Expressionmentioning

confidence: 99%

Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes

Lykke‐Andersen

Jensen

2015

Nat Rev Mol Cell Biol

664

567

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Nonsense-mediated mRNA decay (NMD) is probably the best characterized eukaryotic RNA degradation pathway. Through intricate steps, a set of NMD factors recognize and degrade mRNAs with translation termination codons that are positioned in abnormal contexts. However, NMD is not only part of a general cellular quality control system that prevents the production of aberrant proteins. Mammalian cells also depend on NMD to dynamically adjust their transcriptomes and their proteomes to varying physiological conditions. In this Review, we discuss how NMD targets mRNAs, the types of mRNAs that are targeted, and the roles of NMD in cellular stress, differentiation and maturation processes.

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The Upf Factor Complex Interacts with Aberrant Products Derived from mRNAs Containing a Premature Termination Codon and Facilitates Their Proteasomal Degradation

Cited by 26 publications

References 36 publications

Gentamicin-Induced Readthrough and Nonsense-Mediated mRNA Decay of SERPINB7 Nonsense Mutant Transcripts

Gentamicin-Induced Readthrough and Nonsense-Mediated mRNA Decay of SERPINB7 Nonsense Mutant Transcripts

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

Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes

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