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Masking of a nuclear signal motif by monoubiquitination leads to mislocalization and degradation of the regulatory enzyme cytidylyltransferase.

http://www.ncbi.nlm.nih.gov/pubmed/19332566

Monoubiquitination aids in the nuclear export and entrance of proteins into the lysosomal degradative pathway, although the mechanisms are unknown. Cytidylyltransferase (CCTalpha) is a proteolytically sensitive lipogenic enzyme containing an NH(2)-terminal nuclear localization signal (NLS). We show here that CCTalpha is monoubiquitinated at a molecular site (K(57)) juxtaposed near its NLS, resulting in disruption of its interaction with importin-alpha, nuclear exclusion, and subsequent degradation within the lysosome. Cellular expression of a CCTalpha-ubiquitin fusion protein that mimics the monoubiquitinated enzyme resulted in cytoplasmic retention. A CCTalpha K(57R) mutant exhibited an extended half-life, was retained in the nucleus, and displayed proteolytic resistance. Importantly, by using CCTalpha-ubiquitin hybrid constructs that vary in the intermolecular distance between ubiquitin and the NLS, we show that CCTalpha monoubiquitination masks its NLS, resulting in cytoplasmic retention. These results unravel a unique molecular mechanism whereby monoubiquitination governs the trafficking and life span of a critical regulatory enzyme in vivo.

Pubmed ID: 19332566 RIS Download

Mesh terms: Amino Acid Motifs | Amino Acid Sequence | Animals | Cell Nucleus | Choline-Phosphate Cytidylyltransferase | Endosomes | Enzyme Stability | Half-Life | Lysine | Lysosomes | Mice | Molecular Sequence Data | Mutant Proteins | Nuclear Localization Signals | Protein Binding | Protein Processing, Post-Translational | Protein Transport | Rats | Structure-Activity Relationship | Tumor Necrosis Factor-alpha | Ubiquitination | alpha Karyopherins

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Associated grants

  • Agency: NHLBI NIH HHS, Id: R01 HL068135
  • Agency: NHLBI NIH HHS, Id: R01 HL081784
  • Agency: NHLBI NIH HHS, Id: R01 HL097376

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