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@ARTICLE{Hans:140270,
      author       = {Hans, Friederike and Eckert, Marita and von Zweydorf, Felix
                      and Gloeckner, Christian Johannes and Kahle, Philipp J},
      title        = {{I}dentification and characterization of ubiquitinylation
                      sites in {TAR} {DNA}-binding protein of 43 k{D}a
                      ({TDP}-43).},
      journal      = {The journal of biological chemistry},
      volume       = {293},
      number       = {41},
      issn         = {0021-9258},
      address      = {Bethesda, Md.},
      publisher    = {Soc.60645},
      reportid     = {DZNE-2020-06592},
      pages        = {16083-16099},
      year         = {2018},
      abstract     = {TAR DNA-binding protein of 43 kDa (TDP-43) forms
                      pathological aggregates in neurodegenerative diseases,
                      particularly in certain forms of frontotemporal dementia and
                      amyotrophic lateral sclerosis. Pathological modifications of
                      TDP-43 include proteolytic fragmentation, phosphorylation,
                      and ubiquitinylation. A pathognomonic TDP-43 C-terminal
                      fragment (CTF) spanning amino acids 193-414 contains only
                      four lysine residues that could be potentially
                      ubiquitinylated. Here, serial mutagenesis of these four
                      lysines to arginine revealed that not a single residue is
                      responsible for the ubiquitinylation of mCherry-tagged CTF.
                      Removal of all four lysines was necessary to suppress
                      ubiquitinylation. Interestingly, Lys-408 substitution
                      enhanced the pathological phosphorylation of the immediately
                      adjacent serine residues 409/410 in the context of
                      mCherry-CTF. Thus, Lys-408 ubiquitinylation appears to
                      hinder Ser-409/410 phosphorylation in TDP-43 CTF. However,
                      we did not observe the same effect for full-length TDP-43.
                      We extended the mutagenesis study to full-length TDP-43 and
                      performed MS. Ubiquitinylated lysine residues were
                      identified in the nuclear localization sequence (NLS; Lys-84
                      and Lys-95) and RNA-binding region (mostly Lys-160, Lys-181,
                      and Lys-263). Mutagenesis of Lys-84 confirmed its importance
                      as the major determinant for nuclear import, whereas Lys-95
                      mutagenesis did not significantly affect TDP-43's
                      nucleo-cytoplasmic distribution, solubility, aggregation,
                      and RNA-processing activities. Nevertheless, the K95A mutant
                      had significantly reduced Ser-409/410 phosphorylation,
                      emphasizing the suspected interplay between TDP-43
                      ubiquitinylation and phosphorylation. Collectively, our
                      analysis of TDP-43 ubiquitinylation sites indicates that the
                      NLS residues Lys-84 and Lys-95 have more prominent roles in
                      TDP-43 function than the more C-terminal lysines and
                      suggests a link between specific ubiquitinylation events and
                      pathological TDP-43 phosphorylation.},
      keywords     = {Active Transport, Cell Nucleus / Cell Nucleus: metabolism /
                      DNA-Binding Proteins: chemistry / DNA-Binding Proteins:
                      genetics / DNA-Binding Proteins: metabolism / HEK293 Cells /
                      Humans / Lysine: chemistry / Mutagenesis, Site-Directed /
                      Mutation / Phosphorylation / Protein Processing,
                      Post-Translational / Solubility / Ubiquitin: metabolism /
                      DNA-Binding Proteins (NLM Chemicals) / TDP-43 protein, human
                      (NLM Chemicals) / Ubiquitin (NLM Chemicals) / Lysine (NLM
                      Chemicals)},
      cin          = {AG Kahle / AG Gloeckner},
      ddc          = {540},
      cid          = {I:(DE-2719)1210000-4 / I:(DE-2719)1210007},
      pnm          = {345 - Population Studies and Genetics (POF3-345)},
      pid          = {G:(DE-HGF)POF3-345},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30120199},
      pmc          = {pmc:PMC6187624},
      doi          = {10.1074/jbc.RA118.003440},
      url          = {https://pub.dzne.de/record/140270},
}