Objective
Eukaryotic cells organize different functions into special compartments, the organelles. The advantages for the cell to maintain such structures is obvious since they increase the efficiency of certain metabolic processes by creating unique microenvironments with specific chemical properties and by allowing control over certain metabolic pathways. The price is high, however, since the cell has to invest in the generation and maintenance of these organelles. In addition, it is of utmost importance that the physiological functions of the various organelles are optimally adapted to the requirements of the cell in which they occur. One of the important means to achieve this is to precisely adjust the number and size of the organelles present per cell, a process called organellar homeostasis. The unraveling of the complex mechanisms of this process is one of the main challenges of modern cell biology.
This proposal aims to resolve the principles of peroxisome biogenesis and degradation in yeast with the ultimate goal to obtain insight in the homeostasis of the organelle. Yeast peroxisomes are ideally suited for such studies for various reasons. Of all organelles, peroxisomes are the simplest in their mode of development and construction. The model organisms, yeasts, are easy to cultivate with relative short doubling times (1 - 4 h) and the proliferation and physiological function of their peroxisomes can be precisely prescribed by manipulation of the growth conditions. Thus, the number of organelles per cell and their enzymic contents are controlled and can be adapted on request. Also the opposite process, namely the selective degradation of peroxisomes can be specifically induced by shifting induced cells to conditions in which the organelles are no longer required for growth. In methylotrophic yeasts furthermore the rate and kinetics of degradation can be controlled. Moreover, yeasts are unique in a sense that they can grow in the absence of intact peroxisomes under specific conditions. Accordingly, ideal conditions are now available to initiate studies on peroxisome appearance/disappearance which are not available for other organelles.
Importantly, many genes essential for peroxisome biogenesis (termed PEX genes) have now become available from the analysis of mutants, defective in these organelles. Similarly, the first genes essential for peroxisome degradation (termed PDD) have now been isolated.
The proposed work is a logical continuation of the currently ongoing INTAS programme of the same team. The results of the research in this programme have provided the building blocks for the new programme (e.g. technical skills, mutants, genes, antisera) and have led to the first mutual publications on peroxisome degradation. This work also provided the insight that has led to the extension of the proposal, namely that peroxisome biogenesis and degradation share common elements and may converge at the level of Pex14p, a protein initially identified as the docking protein essential peroxisomal matrix protein import. Accordingly, this now opens the way to study peroxisome homeostasis at the level of the regulation of the import machinery.
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9750 AA Haren
Netherlands