Novel regulators of endosome dynamics, MHCII antigen presentation and chemosensitivity

Wijdeven, R.H.M. (2017)

Doctoral Thesis

The aim of my work was to identify novel proteins that are involved in different aspects of disease biology, in the hope that we can target these to treat the disease. Using large-scale screening technologies, I found a novel regulator of chemosensitivity to the anti-cancer drugs etoposide and doxorubicin. Furthermore, novel proteins and drugs that target MHCII antigen presentation were picked up. Interestingly, one of these drugs is currently used in the clinic to treat MHCII-dependent autoimmune diseases, but for which the mechanism of action is unknown. Lastly, these screens yielded enzymes that control the dynamics of endosomes in the cell, which can potentially be targeted in cancers that rely on overactivation of growth signaling receptors. Taken together, my work has provided new potential targets for the treatment or classification of several tumor types, as well as a potential mechanism of action for a widely used drug.

• Endosome Biology
• MHCII antigen presentation
• Doxorubicin
• SWI/SNF
• OTUD1
• USP54
• Keap1
• RNF26
• ORP1L

• All authors: Wijdeven, R.H.M.
• Supervisor: Neefjes, J.J.C.
• Co-supervisor: Overkleeft, H.S.
• Committee: Borst, J.; Dijke, P. ten; Ovaa, H.; Reits, E.A.J.; Zwart, W.T.
• Qualification: Doctor (dr.)
• Awarding Institution: Chemische Immunologie, Medicine / Leiden University Medical Center (LUMC), Leiden University
• Date: 2017-11-29
• ISBN (print): 9789462337701