title: TMP21 degradation is mediated by the ubiquitin-proteasome pathway.
abstract: The presenilin-associated complex regulates two independent intramembranous cleavage activities, i.e. gamma-secretase and epsilon-secretase activity. The gamma-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 gamma-secretase activity, resulting in increased amyloid beta protein 40 and 42, without affecting the epsilon-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 gamma-secretase complex members, is mediated by the ubiquitin-proteasome pathway.
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Shengchun
authors.initials: S
authors.lastname: Liu
authors.forename: Kelley
authors.initials: K
authors.lastname: Bromley-Brits
authors.forename: Kun
authors.initials: K
authors.lastname: Xia
authors.forename: Jill
authors.initials: J
authors.lastname: Mittelholtz
authors.forename: Ruitao
authors.initials: R
authors.lastname: Wang
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000201:enzymology; D029543:Nucleocytoplasmic Transport Proteins; D053763:Presenilins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D029543:Nucleocytoplasmic Transport Proteins; D053763:Presenilins; D061988:Proteasome Inhibitors; C484395:TMED10 protein, human; D025801:Ubiquitin; D053829:Amyloid Precursor Protein Secretases; D046988:Proteasome Endopeptidase Complex