title: Cerebral small vessel disease-related protease HtrA1 processes latent TGF-β binding protein 1 and facilitates TGF-β signaling.
abstract: High temperature requirement protein A1 (HtrA1) is a primarily secreted serine protease involved in a variety of cellular processes including transforming growth factor β (TGF-β) signaling. Loss of its activity causes cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), an inherited form of cerebral small vessel disease leading to early-onset stroke and premature dementia. Dysregulated TGF-β signaling is considered to promote CARASIL pathogenesis, but the underlying molecular mechanisms are incompletely understood. Here we present evidence from mouse brain tissue and embryonic fibroblasts as well as patient skin fibroblasts for a facilitating role of HtrA1 in TGF-β pathway activation. We identify latent TGF-β binding protein 1 (LTBP-1), an extracellular matrix protein and key regulator of TGF-β bioavailability, as a novel HtrA1 target. Cleavage occurs at physiological protease concentrations, is prevented under HtrA1-deficient conditions as well as by CARASIL mutations and disrupts both LTBP-1 binding to fibronectin and its incorporation into the extracellular matrix. Hence, our data suggest an attenuation of TGF-β signaling caused by a lack of HtrA1-mediated LTBP-1 processing as mechanism underlying CARASIL pathogenesis.
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilians University, 81377 Munich, Germany;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Beaufort
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilians University, 81377 Munich, Germany;
authors.forename: Eva
authors.initials: E
authors.lastname: Scharrer
authors.affiliation: Institute of Molecular Immunology, Helmholtz-Zentrum München, 81377 Munich, Germany;
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.affiliation: Centre for Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, 45141 Essen, Germany;
authors.forename: Vanda
authors.initials: V
authors.lastname: Lux
authors.affiliation: Centre for Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, 45141 Essen, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Ehrmann
authors.affiliation: Centre for Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, 45141 Essen, Germany; Emeritus Group Structure Research, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany; Center for Integrated Protein Science at the Department of Chemistry, Lehrstuhl für Biochemie, Technische Unversität München, 85748 Garching, Germany; School of Biosciences, Cardiff University, Cardiff CF10 3US, Wales, United Kingdom; christof.haffner@med.uni-muenchen.de huber@biochem.mpg.de martin.dichgans@med.uni-muenchen.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Huber
authors.affiliation: Department of Molecular Neuroscience and Neurogenetics Laboratory, University College London (UCL) Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London WC1N 3BG, United Kingdom;
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: Stroke Research Group, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London WC1N 3BG, United Kingdom; and.
authors.forename: David
authors.initials: D
authors.lastname: Werring
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilians University, 81377 Munich, Germany; christof.haffner@med.uni-muenchen.de huber@biochem.mpg.de martin.dichgans@med.uni-muenchen.de.
authors.forename: Christof
authors.initials: C
authors.lastname: Haffner
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilians University, 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany christof.haffner@med.uni-muenchen.de huber@biochem.mpg.de martin.dichgans@med.uni-muenchen.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
mesh_terms: D000505:Alopecia / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000235:genetics* / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics / Q000502:physiology*; D056784:Leukoencephalopathies / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D017354:Point Mutation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D058258:Serpin E2 / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D012867:Skin; D013122:Spinal Diseases / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: C526318:CCN2 protein, mouse; D005353:Fibronectins; C509032:LTBP1 protein, human; D053779:Latent TGF-beta Binding Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; C492073:HtrA1 protein, mouse; D012697:Serine Endopeptidases
keywords: LTBP-1; extracellular matrix; proteolysis; small vessel disease