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TMP21 degradation is mediated by the ubiquitin-proteasome pathway

Authors

  • Shengchun Liu,

    1. Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada
    2. Department of Surgery, The First Affiliated Hospital, Chongqing University of Medical Sciences, Chongqing, China
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    • *

      These authors contributed equally to this study.

  • Kelley Bromley-Brits,

    1. Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada
    2. Graduate Program in Neuroscience, The University of British Columbia, Vancouver, BC, Canada
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    • *

      These authors contributed equally to this study.

  • Kun Xia,

    1. National Laboratory of Medical Genetics of China, Central South University, Changsha, Hunan, China
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    • *

      These authors contributed equally to this study.

  • Jill Mittelholtz,

    1. Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada
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  • Ruitao Wang,

    1. Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada
    2. Department of Geriatrics, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China
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  • Weihong Song

    1. Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada
    2. Graduate Program in Neuroscience, The University of British Columbia, Vancouver, BC, Canada
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Dr Weihong Song, 1Townsend Family Laboratories, as above.
E-mail: weihong@interchange.ubc.ca

Abstract

The presenilin-associated complex regulates two independent intramembranous cleavage activities, i.e. γ-secretase and ε-secretase activity. The γ-secretase complex requires four critical components for its activity: presenilin 1, anterior pharynx-defective 1, nicastrin 1 and presenilin enhancer 2, all of which are degraded through the ubiquitin-proteasome pathway. Recently, TMP21, a type I transmembrane protein involved in endoplasmic reticulum/Golgi transport, was identified as a member of the presenilin complex. Knockdown of TMP21 selectively regulated pathogenic γ-secretase activity, resulting in increased amyloid β protein 40 and 42, without affecting the ε-cleavage of Notch. A further understanding of TMP21 degradation is required to examine the biological consequences of TMP21 protein level aberrations and their potential role in the pathogenesis of Alzheimer’s disease and drug development. Here we show that human TMP21 has a short half-life of approximately 3 h. Treatment with proteasomal inhibitors can increase TMP21 protein levels in both a time- and dose-dependent manner, and both co-immunoprecipitation and immunofluorescent staining show that TMP21 is ubiquitinated. Inhibition of the lysosomal pathway failed to show a dose-dependent increase in TMP21 protein levels. Taken together, these results indicate that the degradation of TMP21, as with the other presenilin-associated γ-secretase complex members, is mediated by the ubiquitin-proteasome pathway.

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