HtrA1-dependent proteolysis of TGF-β controls both neuronal maturation and developmental survival

Abstract

Transforming growth factor-b (TGF-b) signalling controls a number of cerebral functions and dysfunctions including synaptogenesis, amyloid-b accumulation, apoptosis and excitotoxicity. Using cultured cortical neurons prepared from either wild type or transgenic mice overexpressing a TGF-b-responsive luciferase reporter gene (SBE-Luc), we demonstrated a progressive loss of TGF-b signalling during neuronal maturation and survival. Moreover, we showed that neurons exhibit increasing amounts of the serine protease HtrA1 (high temperature responsive antigen 1) and corresponding cleavage products during both in vitro neuronal maturation and brain development. In parallel of its ability to promote degradation of TGF-b1, we demonstrated that blockage of the proteolytic activity of HtrA1 leads to a restoration of TGF-b signalling, subsequent overexpression of the serpin type -1 plasminogen activator inhibitor (PAI-1) and neuronal death. Altogether, we propose that the balance between HtrA1 and TGF-b could be one of the critical events controlling both neuronal maturation and developmental survival.

Features of Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

“…In contrast, it has been reported that HTRA1 cleaves mature TGF-β1 or TGF-β1 receptors in extracellular space. 31,36,37 However, all results in regard to the downregulation of TGF-β signaling by HTRA1 were obtained by the overexpression conditions; thus, the downregulation mechanism under physiological conditions is still unclear.…”

“…The TGF-β dimer binds to TGF-β receptor. HTRA1 might cleave (A) proTGF-β, 30 (B) TGF-β dimer, 31,36 (C) TGF-β receptor, 37 or (D) extracellular matrix proteins. 26 The cleaved products are degradated, resulting in the reduction of TGF-β signaling.…”

Serine Protease HtrA1 Associates with Microtubules and Inhibits Cell Migration

“…However, HtrA1 is the first in the family to be implicated as a tumor suppressor in ovarian cancer and melanoma (3,5,13). In addition, HtrA1 is implicated in various pathogenic and developmental processes, including osteoarthritis, Alzheimer's disease, neuronal maturation and development, age-related macular degeneration, and tumor progression (11,23,24,33,36,50,56). Specific to its role in tumor progression, HtrA1 is downregulated in various cancers, and its downregulation is associated with resistance to chemotherapy and a metastatic phenotype (4,11,19).…”

HTRA1 (HtrA serine peptidase 1)

“…It was demonstrated that the proteolytic activity of HtrA1 is indispensable for this inhibitory function (Oka et al, 2004). Recent studies showed also that TGF-beta1 is a substrate for HtrA1 in vitro (Launay et al, 2008). However, a hypothesis that degradation of TGF-beta proteins is the underlying mechanism of TGF-beta signaling regulation by HtrA1 needs further studies.…”