Master of Science in Molecular Medicin Birendra Kumar Shrestha disputerer for ph.d.-graden i helsevitenskap og vil offentlig forsvare avhandlingen:
“Regulation of Autophagy-related proteins: Roles of post-translational modifications”
Kort populærvitenskapelig sammendrag av avhandlingen:
Autophagy is a self-renovation system used by cells to degrade harmful misfolded proteins and damaged organelles for recycling of essential building blocks in the cells. The cellular contents to be degraded are tagged and recruited within a double-membrane structure called the autophagosome. The autophagosome fuses with lysosomes. The lysosome contains acid hydrolases for degrading the cellular contents coming in following fusion with autophagosomes. The dysregulation of autophagy is associated with cancer, infection, inflammation, aging, osteoporosis, neurodegenerative and metabolic diseases. So, a better understanding of the autophagy pathway may help us design new drugs and therapies where autophagy is modulated to counteract major diseases.
The Ph.D. thesis project of Birendra Kumar Shrestha was carried out in the Molecular Cancer Research Group (MCRG), Department of Medical Biology, under the supervision of group leader, Prof. Terje Johansen. The study focuses on the effect of post-translational modifications of LC3B and TP53INP2 and also investigates the molecular mechanism involved in ATG4B-mediated cleavage and delipidation of the ATG8 family of autophagy proteins. The ATG8 family proteins are essential for the formation of autophagosomes and fusion of these with lysosomes. The ATG8 family contains six members: LC3A, LC3B, LC3C, GABARAP, GABARAPL1, and GABARAPL2. In this study, it is shown that phosphorylation of LC3B at threonine 50 affects its interaction with several essential autophagy-related proteins and negatively regulates selective autophagy. Selective autophagy is performed by autophagy receptors that can pick out the “garbage” that is to be degraded and recycled and ferry it to the autophagosome.
The autophagy-associated protein, TP53INP2 is involved in regulating autophagosome formation. In this study, we found that the posttranslational modification of a specific lysine residue on TP53INP2 impairs its nuclear import when cells are starved for nutrition. We also found that TP53INP2 is degraded in the cell nucleus by the proteasome. The proteasome is a protein degradation machine that degrades proteins one-by-one after they have received a tag marking them for degradation.
The cysteine protease, ATG4B plays an essential role in the cleavage of ATG8 family proteins at their C-terminal end. The cleavage is followed by the addition of lipid molecules at the cleaved site. The addition of lipid to ATG8 family proteins facilitates their binding to the autophagosomes. After completion of autophagosome formation, such lipid molecules are cleaved off by ATG4B. In this study, we revealed the role of amino acid residues in the C-terminal region of ATG4B that mediates binding to the ATG8 family proteins to facilitate cleavage and delipidation.
Veiledere
Hovedveileder professor Terje Johansen
Biveileder førsteamanuensis Trond Lamark
Biveileder førsteamanuensis Eva Sjøttem
Bedømmelseskomiteen
Ph.D., Principal investigator Maria Lyngaas, Radiumhospitalet, Norge - 1. opponent
Ph.D., Principal investigator Jorrit Enserink, Radiumhospitalet, Norge – 2. opponent
Professor Ole Morten Seternes, Institutt for farmasi, Det helsevitenskapelige fakultet, UiT Norges arktiske universitet – leder av komité
Prøveforelesning over oppgitt emne holdes kl. 10.15, samme sted: “A systems perspective of regulation of autophagy by metabolic intermediates”