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... Show moreThe 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. Show less
Antigen presentation by MHC class II is critical for immune responses against pathogens and tumors. Antigen loading occurs primarily in lysosomal-related organelles (LROs) known as MIICs.... Show moreAntigen presentation by MHC class II is critical for immune responses against pathogens and tumors. Antigen loading occurs primarily in lysosomal-related organelles (LROs) known as MIICs. Ultimately, the MHC II-peptide complexes are transported for cell surface display. Here, we study intracellular transport of MIICs, a poorly understood process in MHC II antigen presentation. We propose that Rab7 lies at the heart of transport by assembling a specific receptor (Rab7-RILP-ORP1L) for the minus end-directed dynein-dynactin motor on the cytosolic face of MIICs/LROs. Full activation of transport requires a second receptor, _III spectrin. Whereas this model explains how Rab7 controls minus end-directed transport, it does not suffice to explain the characteristic pattern of bidirectional motility exhibited by MIICs/LROs. Here, we propose that cholesterol dictates ORP1L conformation which acts as a switch controlling access of dynein-dynactin to Rab7-RILP, thereby regulating LRO positioning, as observed in NPC disease. Rab7-RILP-ORP1L may also integrate transport and tethering of MIICs/LROs, consecutive processes within the endocytic pathway. Show less
