Seminars and Symposia
IDAC Seminar, 15 July 2011
|Secretariat, Alumni Association, IDAC|
|Date||Friday, 15July 2011,16:00～|
|Room||seminar-shitsu（3）, IDAC Research Bldg.|
|Title||HtrA family proteins in Human Diseases|
|Affiliation||Nara Institute of Science and Technology (NAIST), Laboratory of Gene Function in Animals|
|Person-in-charge||Yoshikazu Kuwahara Dept.Pathology (ex 8509)|
|Abstract||HtrA family proteins in Human Diseases
Nara Institute of Science and Technology (NAIST), Laboratory of Gene Function in Animals
HtrA, high temperature requirement A, is a family of serine proteases which are highly conserved from bacteria, plants to humans. E,coli has three HtrA1 proteins called Degs, DegP, and DegQ., which degrade or refold heat-denatured proteins in the periplasm and render the cell heat resistance. There are four HTRA genes in human genome. HTRA2 encodes a mitochondrion-restricted protein involved in quality control of mitochondrial proteins. HTRA1, 3 and 4 are highly homologous and secretory proteins, containing an IGFBP domain and a Kazal type inhibitor domain in their N-terminal.
HtrA1 expression was detected in specific regions of developing skeletal elements such as mesenchymal cells surrounding cartilage nodules, joints, tendons, and ligaments during mouse embryogenesis. It is also reported that HtrA1 is increased in joint cartilage of osteoarthritis patients whose joints show extensive destruction of cartilage ECM. We showed that HtrA1 expression was also induced in a mouse rheumatoid arthritis model. HtrA1 protein was highly deposited in the site where ECM was severely degraded. HtrA1 preferentially degrades proteoglycans (such as biglycan, decorin, aggrecan, and fibromodulin) and glycoproteins (such as fibronectin) in ECM of articular cartilage. We also showed that HtrA1 inhibits signaling of various TGF-b family growth factors which have important roles to maintain joint cartilage healthy. Based on these findings, we hypothesize that HtrA1must be a deteriorating factor for developing arthritis by deregulating metabolism of ECM and the TGF-b signaling. To examine our hypothesis we made HtrA1 KO mice. In this seminar, I will show you the results of analysis of HtrtA1 KO mice.
Human HtrA1 shows close association with onset of other age-related human diseases. SNPs in the promoter region of the HTRA1 gene show a strong linkage to the onset of age-related macular degeneration (AMD), which is the leading cause of blindness of elderly people in Europe and the US. Loss of function mutation of human HTRA1 is associated with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
Molecular analysis of HtrA proteins should give us clues to understand pathogenesis of various age-related human diseases and lead us to development of effective therapies for these diseases.