title: Human high temperature requirement serine protease A1 (HTRA1) degrades tau protein aggregates.
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.
authors.affiliation: Centre for Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Universitaetsstrasse, 45141 Essen, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Tennstaedt
authors.forename: Simon
authors.initials: S
authors.lastname: Pöpsel
authors.forename: Linda
authors.initials: L
authors.lastname: Truebestein
authors.forename: Patrick
authors.initials: P
authors.lastname: Hauske
authors.forename: Anke
authors.initials: A
authors.lastname: Brockmann
authors.forename: Nina
authors.initials: N
authors.lastname: Schmidt
authors.forename: Inga
authors.initials: I
authors.lastname: Irle
authors.forename: Barbara
authors.initials: B
authors.lastname: Sacca
authors.forename: Christof M
authors.initials: CM
authors.lastname: Niemeyer
authors.forename: Roland
authors.initials: R
authors.lastname: Brandt
authors.forename: Hanna
authors.initials: H
authors.lastname: Ksiezak-Reding
authors.forename: Anca Laura
authors.initials: AL
authors.lastname: Tirniceriu
authors.forename: Rupert
authors.initials: R
authors.lastname: Egensperger
authors.forename: Alfonso
authors.initials: A
authors.lastname: Baldi
authors.forename: Leif
authors.initials: L
authors.lastname: Dehmelt
authors.forename: Markus
authors.initials: M
authors.lastname: Kaiser
authors.forename: Robert
authors.initials: R
authors.lastname: Huber
authors.forename: Tim
authors.initials: T
authors.lastname: Clausen
authors.forename: Michael
authors.initials: M
authors.lastname: Ehrmann
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016501:Neurites / Q000201:enzymology / Q000473:pathology; D017510:Protein Folding; D059748:Proteolysis; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D024801:Tauopathies / Q000201:enzymology / Q000473:pathology; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D009419:Nerve Tissue Proteins; D016875:tau Proteins; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases