Distribution of the Serine Protease HtrA1 in Normal Human Tissues

Abstract

The human HtrA family of proteases consists of three members: HtrA1, HtrA2, and HtrA3. In bacteria, the chief role of HtrA is recognition and degradation of misfolded proteins in the periplasm, combining a dual activity of chaperone and protease. In humans, the three HtrA homologues appear to be involved in diverse functions such as cell growth, apoptosis, allergic reactions, fertilization, control of blood pressure, and blood clotting. Previous studies using RNA blot hybridization have shown that the expression of HtrA1 is ubiquitous in normal human tissues. Here we show by immunohistochemistry (IHC) that HtrA1 is widely expressed, although different tissue distributions and/or levels of expression were detected in the different tissues examined. In particular, high to medium HtrA1 expression was detected in mature layers of epidermis, in secretory breast epithelium, in liver, and in kidney tubules of cortex, in concordance with its secretory properties. Furthermore, we show a higher protein expression level in the epithelium of proliferative endometrium, in contrast to epithelium of secretory endometrium, which is almost completely negative for this protein. This suggests a possible role for HtrA1 in the modulation of tissue activity in this organ. The various expression levels in human tissues indicate several possible roles for HtrA1 in different cell types.

Implications of the serine protease HtrA1 in amyloid precursor protein processing

“…HtrA1 was strongly expressed in astrocytes and cortical neurons (Fig. 4 D-F), whereas expression in neuroglial components and neurons of normal adult brains is always very low (33). In particular, the percentage of neurons overexpressing HtrA1 ranged from 1-2% of cerebellum and occipital cortex to 2-4% of frontal, parietal, and temporal cortex and 8-10% of hippocampus.…”

“…4 D-F). In contrast, HtrA1 expression in neuroglial components and neurons of normal adult brains is always very low (33). HtrA1 also colocalizes with ␤-amyloid deposits in human brain samples.…”

Serine protease HtrA1 is developmentally regulated in trophoblast and uterine decidual cells during placental formation in the mouse

“…The functions of other HtrA members are not yet well-understood; however, it has been proposed that they may degrade misfolded, aggregated, or damaged proteins in suboptimal conditions such as during stress (Clausen et al, 2002). HtrA1 expression was identified recently during mouse development (De Luca et al, 2004) and in several human tissues (De Luca et al, 2003), and high expression of HtrA1 was reported in the human placenta (Nie et al, 2003a). Of interest, significant up-regulation of HtrA3 expression was also identified during placentation in the mouse (Nie et al, 2003b), suggesting that HtrA proteases might play important roles in placental development and function.…”

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

“…12 HtrA1, HtrA3 and HtrA4 are secreted proteases. Ubiquitously expressed in normal human adult tissues, 13 HtrA1 contains in addition to a highly conserved protease domain (trypsin like serine protease domain), an insulin growth factor-binding domain, a kazal type S protease inhibitor domain followed by one or two post-synaptic disclarge zona domains and a follistatin-like domain. 10 There is increasing evidences that HtrA1 regulates several physiological and pathological processes including tumour development, 14 Alzheimer's disease (AD), 15 placentation, 16 age-related macular degeneration 17 and osteoarthritis.…”