MYO5B encodes myosin-Vb, known for its role in the recycling of brush border proteins to the cell surface. MYO5B is ubiquitously expressed in various tissues. MYO5B mutations and/or alterations in MYO5B expression have implicated in several diseases. As most commonly known, loss-of-function mutations in MYO5B can cause microvillus inclusion disease (MVID), which is characterized by severe diarrhea and nutrient malabsorption. In addition, the MYO5B-associated recycling endosome system has been implicated in cell mitosis including cytokinesis and spindle orientation. Recently, evidence shows MYO5B is correlated to colorectal cancer (CRC) tumorigenesis and prognosis. However, the mechanism via which mutations/alterations of MYO5B expression lead to these diseases/intracellular dysfunctions is not well understood. The purpose of this thesis was to increase our understanding of the role of MYO5B in MVID, cell division and CRC. Here, we have demonstrated that myosin Vb is important for late endo-lysosomal homeostasis. The resultant hypersensitivity of myosin-Vb-depleted cells to oxidative lysosomal membrane permeabilization and cell death should be considered part of MVID pathogenesis. Further, we have identified a novel molecular mechanism explaining the extensive villus degeneration in MVID and provided preclinical evidence that antioxidant treatment is a promising pharmacological therapeutic option for MVID patients. In addition, we have found that myosin Vb plays a novel role in securing mitotic spindle orientation and epithelial architecture through the regulation of late endosome size. Moreover, we have demonstrated loss function of myosin Vb increases the sensitivity of colorectal cancer cells to cisplatin by alteration of lysosomal membrane integrity.
|Qualification||Doctor of Philosophy|
|Place of Publication||[Groningen]|
|Publication status||Published - 2020|