Human High Temperature Requirement Serine Protease A1 (HTRA1) Degrades Tau Protein Aggregates*

  1. Michael Ehrmanna,j,3
  1. From the aCentre for Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Universitaetsstrasse, 45141 Essen, Germany,
  2. the bFakultät Chemie, Biologisch-Chemische Mikrostrukturtechnik, Technische Universität Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany,
  3. the cFachbereich Biologie/Chemie, University Osnabrueck, D-49076 Osnabrueck, Germany,
  4. the dDepartment of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029,
  5. the eCenter for Neuropathology and Prion Research, Ludwig Maximilians University of Munich, Feodor-Lynen-Strasse 23, 81377 Munich, Germany,
  6. the fDepartment of Biochemistry and Biophysics, Section of Pathology, the Second University of Naples, 80100 Naples, Italy,
  7. the gMax-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany,
  8. the hDepartment for Chemical Biology, Technische Universität Dortmund University, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany,
  9. the iMax-Planck-Institut für Biochemie, Am Klopferspitz 18A, 82152 Martinsried, Germany,
  10. the jSchool of Biosciences, Cardiff University, Cardiff CF10 3US, United Kingdom, and
  11. the kResearch Institute of Molecular Pathology, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria
  1. ↵3 Supported by Deutsche Forschungsgemeinschaft, Alzheimer's Research Trust, the Fonds der Chemischen Industrie, and a grant from the Innovation, Science, Research, and Technology Ministry of Nordrhein-Westfalen, Germany. To whom correspondence should be addressed. Tel.: 49-201-183-2949; E-mail: michael.ehrmann{at}uni-due.de.

  1. ↵1 Both authors contributed equally to this work.

Background: Protein quality control proteases degrade damaged proteins and protein fragments.

Results: The human serine protease HTRA1 degrades tau aggregates and is induced by its substrates.

Conclusion: A member of the widely conserved HtrA family is involved in protein quality control in mammalian cells.

Significance: HTRA1 might function as a tau protease in vivo.

Abstract

Protective proteases are key elements of protein quality control pathways that are up-regulated, for example, under various protein folding stresses. These proteases are employed to prevent the accumulation and aggregation of misfolded proteins that can impose severe damage to cells. The high temperature requirement A (HtrA) family of serine proteases has evolved to perform important aspects of ATP-independent protein quality control. So far, however, no HtrA protease is known that degrades protein aggregates. We show here that human HTRA1 degrades aggregated and fibrillar tau, a protein that is critically involved in various neurological disorders. Neuronal cells and patient brains accumulate less tau, neurofibrillary tangles, and neuritic plaques, respectively, when HTRA1 is expressed at elevated levels. Furthermore, HTRA1 mRNA and HTRA1 activity are up-regulated in response to elevated tau concentrations. These data suggest that HTRA1 is performing regulated proteolysis during protein quality control, the implications of which are discussed.

Footnotes

  • Received October 27, 2011.
  • Revision received April 24, 2012.
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  1. First Published on April 25, 2012 doi: 10.1074/jbc.M111.316232 The Journal of Biological Chemistry 287, 20931-20941.
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