Disease-associated roles of two 2-oxoglutarate dependent dioxygenases, transmembrane prolyl 4-hydroxylase and lysyl hydroxylase 3
Thesis event information
Date and time of the thesis defence
Place of the thesis defence
Leena Palotie Hall 101A, Aapistie 5A, Oulu
Topic of the dissertation
Disease-associated roles of two 2-oxoglutarate dependent dioxygenases, transmembrane prolyl 4-hydroxylase and lysyl hydroxylase 3
Doctoral candidate
Master of Science Subodh Sharma
Faculty and unit
University of Oulu Graduate School, Faculty of Biochemistry and Molecular Medicine, ECM & Hypoxia
Subject of study
Biochemistry and Molecular Medicine
Opponent
Professor Ben Wielockx, Technical University of Dresden
Custos
Professor Johanna Myllyharju, University of Oulu
Disease-associated roles of two 2-oxoglutarate dependent dioxygenases, transmembrane prolyl 4-hydroxylase and lysyl hydroxylase 3
2-Oxoglutarate dependent dioxygenase (2-OGDD) superfamily consists of several enzymes that have diverse roles in various biological processes, for example, the oxygen-dependent regulation of hypoxia-responsive HIFs, post-translational modifications of collagens, DNA demethylation, and other cellular functions. Transmembrane prolyl 4-hydroxylase (P4H-TM) is one of the prolyl 4-hydroxylases (P4Hs), but its function is largely unknown. The current results using astrocytes isolated from P4H-TM knockout mice revealed that P4H-TM is a major regulator of calcium signaling in mouse astrocytes. Our data also demonstrated that the P4H-TM-regulated calcium signaling is mediated by HIF1 and not HIF2. We also showed that P4H-TM is important in maintaining brain homeostasis in an in vivo stroke model. Its inactivation during cerebral ischemia in mice had detrimental consequences causing increased inflammatory microgliosis and neutrophil infiltration. In addition, the permeability of blood-brain-barrier was disrupted in the P4H-TM knockout mice. Thus, instead of protective effects, the inactivation of P4H-TM has certain adverse effects on the ischemic mouse brain.
Another member of the 2-OGDD superfamily, lysyl hydroxylase 3 (LH3) is one of the three LH isoenzymes involved in collagen biosynthesis. Mutations in PLOD3 gene have been identified to cause a connective tissue disorder that affects many tissues. We show here that the PLOD3 disorder is commonly associated with reduced glucosyltransferase (GGT) activity, whereas the contribution of a reduced LH activity remains unclear. Lower GGT activity was shown to result from reduced specific GGT activity, or dimerization defects, or enzyme stability problems of LH3.
These data provide novel insights into the functions of P4H-TM and LH3 and their roles in the pathologic conditions of the HIDEA syndrome and PLOD3 disease, respectively, but further studies are needed to develop therapeutic interventions to manage the conditions.
Another member of the 2-OGDD superfamily, lysyl hydroxylase 3 (LH3) is one of the three LH isoenzymes involved in collagen biosynthesis. Mutations in PLOD3 gene have been identified to cause a connective tissue disorder that affects many tissues. We show here that the PLOD3 disorder is commonly associated with reduced glucosyltransferase (GGT) activity, whereas the contribution of a reduced LH activity remains unclear. Lower GGT activity was shown to result from reduced specific GGT activity, or dimerization defects, or enzyme stability problems of LH3.
These data provide novel insights into the functions of P4H-TM and LH3 and their roles in the pathologic conditions of the HIDEA syndrome and PLOD3 disease, respectively, but further studies are needed to develop therapeutic interventions to manage the conditions.
Last updated: 23.1.2024