טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentGottfried Yossi
SubjectARTS Mechanism of Apoptotic Function and its Involvement in
Selected Pathological Syndromes
DepartmentDepartment of Medicine
Supervisor Ms. Sarit Larisch
Full Thesis textFull thesis text - English Version


Abstract

ARTS is an exceptional member of the septin family of proteins that localizes in the mitochondria and functions as a pro-apoptotic protein. The main goal of my thesis was to determine the mechanism of ARTS apoptotic function. I found that ARTS induces caspase activation through binding and antagonizing IAPS (Inhibitor of Apoptosis Proteins). Moreover, that ARTS caused the reduction of XIAP levels through increased ubiquitin mediated degradation. Though ARTS binds to the BIR3 domain of XIAP similarly to caspase-9 and SMAC/Diablo, ARTS binds to a different sequence within BIR3 and with a unique binding site. In contrast to all other known IAP-antagonists, ARTS does not contain an IBM- (IAP-binding motif). Instead, ARTS uses its unique C' terminus domain not found in any other protein, to binds specifically to BIR3 in XIAP and promote caspase activation.  In living cells, ARTS is a very short-lived protein whose levels are tightly regulated through the ubiquitin-proteasome system. Upon apoptotic induction, ARTS ubiquitination is inhibited, causing increased stability and upregulation of ARTS levels, which in turn leads to increased binding to XIAP and apoptotic cell death.  I found that XIAP serves as an E3-ubiquitin ligase for ARTS, regulating ARTS protein levels in non-apoptotic cells.  ARTS is partly located within the outer membrane of the mitochondria, while its N'-terminus tail protrudes into the cytosol. Under apoptotic conditions ARTS protein is cleaved at its N'-terminus, probably by caspases. According to these data, we suggest that the binding of ARTS to XIAP functions differently under normal and apoptotic conditions, and that the N’-terminus cleavage is involved in regulating ARTS apoptotic function. In the second part of my thesis, ARTS involvement in two brain pathological syndromes was examined: astrocytic tumors and schizophrenia. In astrocytic tumors, a direct correlation was found between the expression of ARTS, malignancy grade and survival rate. We suggest that ARTS may be useful both as a prognostic marker and as a therapeutic tool for patients with astrocytoma. Examination of ARTS expression in post-mortem brains of schizophrenic patients revealed that ARTS was absent in the majority of these samples. It was concluded that the absence of ARTS in schizophrenic brains could be indicative of the role of ARTS and apoptosis in the pathogenesis of schizophrenia.