The OFD1 protein is codified by the gene mutated in Oral facial digital syndrome type I, a rare developmental disorder ascribed to the growing number of diseases associated to cilia dysfunction. OFD1 encodes for a centrosomal/basal body protein required for formation of primary cilia, sensory organelles present on the cell surface of almost all mammalian cells. A cross talk between autophagy and primary cilia has recently emerged. By using a variety of in vivo and in vitro approaches, I demonstrated that, contrary to what shown for other cilioproteins, OFD1 depletion results in autophagy enhancement and increased autophagosomes biogenesis. In addition, the results obtained indicate that OFD1 acts by regulating the stability of the ULK1 complex which plays a critical role in autophagy initiation. Loss of OFD1 impairs degradation of ULK1 complex components (e.g. ULK1 and ATG13) thus promoting ULK1 kinase activity and enhancing autophagosome biogenesis. The identification of LC3 interacting regions (LIR) in the OFD1 protein sequence suggest that OFD1 may function as a selective autophagy receptor for ATG13 by mediating ATG13 degradation through LC3 interaction. One of the main features of ciliopathies, including OFD type I syndrome, is the presence of renal cystic disease. Conditional renal inactivation of Atg7, an essential gene for autophagy, caused a significant reduction in the number of cysts in mutant kidneys of an Ofd1 mouse model. In line with these observations, treatment with chloroquine, an autophagy inhibitor already used in clinical practice, showed a beneficial effect on the renal cystic phenotype observed in a murine Ofd1 model, suggesting that increased autophagy might be associated to renal cystogenesis. The modulation of autophagy, alone or combined with other treatments, could represent a therapeutic approach in renal cystic disease.

THE CENTROSOMAL OFD1 PROTEIN REGULATES AUTOPHAGY INDUCTION / U. Formisano ; internal supervisor: C. Settembre ; external supervisor: A. Boletta. - : . Universita' degli Studi di MILANO, 2019 Jan 28. ((30. ciclo, Anno Accademico 2018. [10.13130/formisano-umberto_phd2019-01-28].

THE CENTROSOMAL OFD1 PROTEIN REGULATES AUTOPHAGY INDUCTION

U. Formisano
2019-01-28

Abstract

The OFD1 protein is codified by the gene mutated in Oral facial digital syndrome type I, a rare developmental disorder ascribed to the growing number of diseases associated to cilia dysfunction. OFD1 encodes for a centrosomal/basal body protein required for formation of primary cilia, sensory organelles present on the cell surface of almost all mammalian cells. A cross talk between autophagy and primary cilia has recently emerged. By using a variety of in vivo and in vitro approaches, I demonstrated that, contrary to what shown for other cilioproteins, OFD1 depletion results in autophagy enhancement and increased autophagosomes biogenesis. In addition, the results obtained indicate that OFD1 acts by regulating the stability of the ULK1 complex which plays a critical role in autophagy initiation. Loss of OFD1 impairs degradation of ULK1 complex components (e.g. ULK1 and ATG13) thus promoting ULK1 kinase activity and enhancing autophagosome biogenesis. The identification of LC3 interacting regions (LIR) in the OFD1 protein sequence suggest that OFD1 may function as a selective autophagy receptor for ATG13 by mediating ATG13 degradation through LC3 interaction. One of the main features of ciliopathies, including OFD type I syndrome, is the presence of renal cystic disease. Conditional renal inactivation of Atg7, an essential gene for autophagy, caused a significant reduction in the number of cysts in mutant kidneys of an Ofd1 mouse model. In line with these observations, treatment with chloroquine, an autophagy inhibitor already used in clinical practice, showed a beneficial effect on the renal cystic phenotype observed in a murine Ofd1 model, suggesting that increased autophagy might be associated to renal cystogenesis. The modulation of autophagy, alone or combined with other treatments, could represent a therapeutic approach in renal cystic disease.
FRANCO, BRUNELLA
Autophagy; lc3; ofd1; polycystic kidney; cystic kidney; oral facial digital; cilioprotein; ciliopathy; primary cilia; selective autophagy; lir; ulk1; atg13; fip200
Settore BIO/18 - Genetica
THE CENTROSOMAL OFD1 PROTEIN REGULATES AUTOPHAGY INDUCTION / U. Formisano ; internal supervisor: C. Settembre ; external supervisor: A. Boletta. - : . Universita' degli Studi di MILANO, 2019 Jan 28. ((30. ciclo, Anno Accademico 2018. [10.13130/formisano-umberto_phd2019-01-28].
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/608763
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