Startseite IsoQC (QPCTL) knock-out mice suggest differential substrate conversion by glutaminyl cyclase isoenzymes
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IsoQC (QPCTL) knock-out mice suggest differential substrate conversion by glutaminyl cyclase isoenzymes

  • Andreas Becker , Rico Eichentopf , Reinhard Sedlmeier , Alexander Waniek , Holger Cynis , Birgit Koch , Anett Stephan , Christoph Bäuscher , Stephanie Kohlmann , Torsten Hoffmann , Astrid Kehlen , Sabine Berg , Ernst-Joachim Freyse , Alexander Osmand , Anne-Christine Plank , Steffen Roßner , Stephan von Hörsten , Sigrid Graubner , Hans-Ulrich Demuth und Stephan Schilling EMAIL logo
Veröffentlicht/Copyright: 19. August 2015
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 397 Heft 1

Abstract

Secretory peptides and proteins are frequently modified by pyroglutamic acid (pE, pGlu) at their N-terminus. This modification is catalyzed by the glutaminyl cyclases QC and isoQC. Here, we decipher the roles of the isoenzymes by characterization of IsoQC-/- mice. These mice show a significant reduction of glutaminyl cyclase activity in brain and peripheral tissue, suggesting ubiquitous expression of the isoQC enzyme. An assay of substrate conversion in vivo reveals impaired generation of the pGlu-modified C-C chemokine ligand 2 (CCL2, MCP-1) in isoQC-/- mice. The pGlu-formation was also impaired in primary neurons, which express significant levels of QC. Interestingly, however, the formation of the neuropeptide hormone thyrotropin-releasing hormone (TRH), assessed by immunohistochemistry and hormonal analysis of hypothalamic-pituitary-thyroid axis, was not affected in isoQC-/-, which contrasts to QC-/-. Thus, the results reveal differential functions of isoQC and QC in the formation of the pGlu-peptides CCL2 and TRH. Substrates requiring extensive prohormone processing in secretory granules, such as TRH, are primarily converted by QC. In contrast, protein substrates such as CCL2 appear to be primarily converted by isoQC. The results provide a new example, how subtle differences in subcellular localization of enzymes and substrate precursor maturation might influence pGlu-product formation.

Keywords: 5-oxo-L-proline; posttranslational modification; pyroglutamate; TRH
Corresponding author: Stephan Schilling, Probiodrug AG, Weinbergweg 22, D-06120 Halle/Saale, Germany, e-mail:
aAndreas Becker and Rico Eichentopf: These authors contributed equally to this work.bPresent address: Fraunhofer Institute for Cell Therapy and Immunology

Acknowledgments

The authors thank D. Friedrich, E. Scheel and H.-H. Ludwig for their excellent technical assistance as well as K. Arendt for critically reading of the manuscript. This work was financially supported by the Investitionsbank Sachsen-Anhalt, grant# 1004/00082 to Probiodrug AG.

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Supplemental Material:

The online version of this article (DOI: 10.1515/hsz-2015-0192) offers supplementary material, available to authorized users.

Received: 2015-6-10
Accepted: 2015-8-12
Published Online: 2015-8-19
Published in Print: 2016-1-1

©2016 by De Gruyter

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. Ancestral protein reconstruction: techniques and applications
  4. Mapping the non-standardized biases of ribosome profiling
  5. Minireview
  6. The macromolecular crowding effect – from in vitro into the cell
  7. Research Articles/Short Communications
  8. Protein Structure and Function
  9. IsoQC (QPCTL) knock-out mice suggest differential substrate conversion by glutaminyl cyclase isoenzymes
  10. Molecular Medicine
  11. Correlated overexpression of metadherin and SND1 in glioma cells
  12. Cell Biology and Signaling
  13. Melanoma differentiation-associated gene 5 is involved in the induction of stress granules and autophagy by protonophore CCCP
  14. Suberoylanilide hydroxamic acid (SAHA) promotes the epithelial mesenchymal transition of triple negative breast cancer cells via HDAC8/FOXA1 signals
  15. Melanocytes are more responsive to IFN-γ and produce higher amounts of kynurenine than melanoma cells
  16. Phenobarbital inhibits calpain activity and expression in mouse hepatoma cells
https://doi.org/10.1515/hsz-2015-0192
Schlagwörter für diesen Artikel
5-oxo-L-proline; posttranslational modification; pyroglutamate; TRH

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. Ancestral protein reconstruction: techniques and applications
  4. Mapping the non-standardized biases of ribosome profiling
  5. Minireview
  6. The macromolecular crowding effect – from in vitro into the cell
  7. Research Articles/Short Communications
  8. Protein Structure and Function
  9. IsoQC (QPCTL) knock-out mice suggest differential substrate conversion by glutaminyl cyclase isoenzymes
  10. Molecular Medicine
  11. Correlated overexpression of metadherin and SND1 in glioma cells
  12. Cell Biology and Signaling
  13. Melanoma differentiation-associated gene 5 is involved in the induction of stress granules and autophagy by protonophore CCCP
  14. Suberoylanilide hydroxamic acid (SAHA) promotes the epithelial mesenchymal transition of triple negative breast cancer cells via HDAC8/FOXA1 signals
  15. Melanocytes are more responsive to IFN-γ and produce higher amounts of kynurenine than melanoma cells
  16. Phenobarbital inhibits calpain activity and expression in mouse hepatoma cells
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