| First Author | Beaufort N | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 46 | Pages | 16496-501 |
| PubMed ID | 25369932 | Mgi Jnum | J:216743 |
| Mgi Id | MGI:5609471 | Doi | 10.1073/pnas.1418087111 |
| Citation | Beaufort N, et al. (2014) Cerebral small vessel disease-related protease HtrA1 processes latent TGF-beta binding protein 1 and facilitates TGF-beta signaling. Proc Natl Acad Sci U S A 111(46):16496-501 |
| abstractText | 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. |
