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Free keywords:
SERINE-PROTEASE, EXTRACELLULAR-MATRIX, FIBRONECTIN, PROTEOLYSIS,
TGF-BETA-1, LTBP-1, ACTIVATION, EXPRESSION, CLEAVAGE, INSIGHTSScience & Technology - Other Topics; small vessel disease, proteolysis, extracellular matrix, LTBP-1;
Abstract:
High temperature requirement protein A1 (HtrA1) is a primarily secreted
serine protease involved in a variety of cellular processes including
transforming growth factor beta (TGF-beta) 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-beta 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-beta pathway activation. We identify
latent TGF-beta binding protein 1 (LTBP-1), an extracellular matrix
protein and key regulator of TGF-beta 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-beta signaling caused by a lack of HtrA1-mediated
LTBP-1 processing as mechanism underlying CARASIL pathogenesis.
