Autophagy-regulated Signalosomes in Cellular Stress and Disease Pathways

A Top Research program project supported by the Research Council of Norway and UiT- The Arctic University of Norway

Our project concerns a cellular process known as autophagy (greek for "self-eating"). Autophagy is a renovation or cleaning process in our cells that helps keeping us healthy and makes it possible for us to enjoy long lives. We are interested in elucidating how autophagy can be targeted, or selective. We want to explore how this selective autophagy is able to regulate signaling systems in our cells.

 

An important challenge for our cells is to properly regulate the potent signaling pathways affecting processes such as cell growth, cell division, inflammation and cell death. Certain signaling pathways are not regulated properly in diseases such as  cancer, diabetes, neurodegeneration, and inflammatory disorders. Proteins can be envisioned as workers and consultants that carry out important functions that are needed to keep our cells alive and healthy. Proteins also make up part of the physical infrastructure in the cells such as the "highways" and various molecular machines. Signaling is often organized into protein complexes containing a number of different proteins acting together in a "signalosome". This organization facilitates sensitive and efficient signaling. As mentioned above, autophagy is a cellular renovation process that serves as a mechanism for degradation and recycling of damaged proteins and non-functional or aged organelles. Autophagy is also called upon under stress conditions, such as starvation. The cell degrades part of itself to recycle building blocks and release energy to ensure its own survival. Recent discoveries implicate autophagy in important specific physiological and pathological processes such as development, immunity, cell death and cancer. Autophagy was regarded as an unspecific process. However, a number of observations suggested that "garbage" could be selected. Work on the scaffold and signaling protein p62 led us to the discovery of selective autophagy at the molecular level. Hence, we found that p62 was as factor that could "sort the garbage". When cells are stressed in various ways we saw that p62 formed dynamic, round bodies in the cells. Our hypothesis is that these bodies represent hubs where signaling involving p62 occurs. They are signalosomes. p62 is, via these signalosomes, involved in regulating formation, integration, transmission, and termination of signaling. To test the hypothesis we will characterize signaling events, the key signaling components, the structural requirements, and the role of selective autophagy in p62 signalosomes. We plan to use knowledge we generate to identify new therapeutic targets for neurodegenerative diseases and cancer.

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