Modulation of chaperone-mediated autophagy by CRAF

While growing, cells generate surplus material that can be used in times of famine or under stress to sustain cell survival. This is done by a mechanism called autophagy, literally meaning eating oneself, that takes place in specialized organelles called lysosomes (literally dissolving organelles). The lysosomes contain factors that transform both other organelles and/or proteins into basic building blocks that can be reused by the cell to build new components or generate energy. The degradation of whole organelles or sections of the cytosol is very well studied. It is called macroautophagy, to indicate that this mechanism degrades large structures. The degradation of soluble proteins occurs with the help of a chaperone which recognizes the proteins to be destroyed and accompanies them to the lysosome where they will be degraded. This mechanism, aptly termed Chaperone-Mediated Autophagy, is estimated to control the amount of about 30% of the proteins in the cell. If Chaperon- Mediate Autophagy goes awry, the consequences for the whole organism are dire, potentially ranging from neurodegeneration to cancer. Thus, to be able to harness Chaperon-Mediate Autophagy for therapeutic purposes, it is essential to learn as much as we can about the mechanisms that regulate it. We have preliminary data that identify the druggable protein CRAF, involved in tumorigenesis, as essential regulator of this kind of autophagy, and want to follow up on these data using biochemistry and cell biology to further explore this connection. Our experiments will provide basic information on the control of autophagy by extracellular signals, and may pave the way for a selective manipulation of protein degradation designed to be beneficial in disease.