Cul5-type Ubiquitin Ligase KLHDC1 Contributes to the Elimination of Truncated SELENOS Produced by Failed UGA/Sec Decoding

Summary The UGA codon signals protein translation termination, but it can also be translated into selenocysteine (Sec, U) to produce selenocysteine-containing proteins (selenoproteins) by dedicated machinery. As Sec incorporation can fail, Sec-containing longer and Sec-lacking shorter proteins co-exist. Cul2-type ubiquitin ligases were recently shown to destabilize such truncated proteins; however, which ubiquitin ligase targets truncated proteins for degradation remained unclear. We report that the Cul5-type ubiquitin ligase KLHDC1 targets truncated SELENOS, a selenoprotein, for proteasomal degradation. SELENOS is involved in endoplasmic reticulum (ER)-associated degradation, which is linked to reactive oxygen species (ROS) production, and the knockdown of KLHDC1 in U2OS cells decreased ER stress-induced cell death. Knockdown of SELENOS increased the cell population with lower ROS levels. Our findings reveal that, in addition to Cul2-type ubiquitin ligases, KLHDC1 is involved in the elimination of truncated oxidoreductase-inactive SELENOS, which would be crucial for maintaining ROS levels and preventing cancer development.

• Publication year

  2020

• Venue

  iScience

• Publication date

  2020-03-07

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.isci.2020.100970PMID 32200094PMCID 7090344
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Scientists rise up against statistical significance

  2019influential reference
• The P Value and Statistical Significance: Misunderstandings, Explanations, Challenges, and Alternatives

  2019influential reference
• Moving to a World Beyond “p < 0.05”

  2019influential reference
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  2019cited by this paper
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  2018cited by this paper
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  2018cited by this paper
• The Eukaryotic Proteome Is Shaped by E3 Ubiquitin Ligases Targeting C-Terminal Degrons.

  2018cited by this paper
• Translation regulation of mammalian selenoproteins.

  2018cited by this paper
• C-Terminal End-Directed Protein Elimination by CRL2 Ubiquitin Ligases.

  2018cited by this paper
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  2014cited by this paper
• Methods to monitor ROS production by fluorescence microscopy and fluorometry.

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  2007cited by this paper
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• Morphogenesis of the Endoplasmic Reticulum: Beyond Active Membrane Expansion

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  2005cited by this paper
• Fluorescence probes used for detection of reactive oxygen species.

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  2004cited by this paper
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• Superoxide reacts with hydroethidine but forms a fluorescent product that is distinctly different from ethidium: potential implications in intracellular fluorescence detection of superoxide.

  2003cited by this paper
• The kelch repeat superfamily of proteins: propellers of cell function.

  2000cited by this paper
• The ER-overload response: activation of NF-kappa B.

  1997cited by this paper
• An isoform of the Golgi t-SNARE, syntaxin 5, with an endoplasmic reticulum retrieval signal.

  1997cited by this paper
• The ER-overload response: activation of NF-κB

  1997cited by this paper
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  1991cited by this paper
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