Cerebral small vessel disease-related protease HtrA1 processes latent TGF-β binding protein 1 and facilitates TGF-β signaling

Beaufort, Nathalie, Scharrer, Eva, Kremmer, Elisabeth, Lux, Vanda, Ehrmann, Michael ORCID: https://orcid.org/0000-0002-1927-260X, Huber, Robert, Houlden, Henry, Werring, David, Haffner, Christof and Dichgans, Martin 2014. Cerebral small vessel disease-related protease HtrA1 processes latent TGF-β binding protein 1 and facilitates TGF-β signaling. Proceedings of the National Academy of Sciences of the United States of America 111 (46) , 16496. 10.1073/pnas.1418087111

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Abstract

Cerebral small vessel disease (SVD) is a major cause of stroke and dementia. Hereditary forms, such as cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), may provide insights into key molecular mechanisms and pathways. The serine protease HtrA1, whose activity is impaired in CARASIL, has been proposed to attenuate TGF-β signaling leading to increased pathway activity in diseased arteries. We analyzed HtrA1-deficient mouse brain tissue and mouse and CARASIL patient fibroblasts and found a reduction in signaling activity on various pathway levels suggesting a facilitating role of HtrA1. Moreover, we identified LTBP-1 as a novel HtrA1 substrate and provide evidence for its functional modulation by HtrA1-dependent proteolysis. Our data suggest down-regulation of TGF-β signaling as a key mechanism underlying CARASIL pathogenesis.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Biosciences
Subjects:	Q Science > QR Microbiology
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Last Modified:	27 Oct 2022 10:02
URI:	https://orca.cardiff.ac.uk/id/eprint/68711

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