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Publication Detail
Cerebral small vessel disease-related protease HtrA1 processes latent TGF-β binding protein 1 and facilitates TGF-β signaling.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Beaufort N, Scharrer E, Kremmer E, Lux V, Ehrmann M, Huber R, Houlden H, Werring D, Haffner C, Dichgans M
  • Publication date:
    18/11/2014
  • Pagination:
    16496, 16501
  • Journal:
    Proc Natl Acad Sci U S A
  • Volume:
    111
  • Issue:
    46
  • Status:
    Published
  • Country:
    United States
  • PII:
    1418087111
  • Language:
    eng
  • Keywords:
    LTBP-1, extracellular matrix, proteolysis, small vessel disease, Alopecia, Animals, Brain, Cells, Cultured, Cerebral Infarction, Connective Tissue Growth Factor, Fibroblasts, Fibronectins, Gene Expression Regulation, HEK293 Cells, High-Temperature Requirement A Serine Peptidase 1, Humans, Latent TGF-beta Binding Proteins, Leukoencephalopathies, Mice, Mice, Knockout, Mutation, Missense, Point Mutation, Protein Binding, Protein Interaction Mapping, Protein Processing, Post-Translational, RNA, Messenger, Recombinant Fusion Proteins, Serine Endopeptidases, Serpin E2, Signal Transduction, Skin, Spinal Diseases, Transfection, Transforming Growth Factor beta1
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.
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