RNA by autophagy
In autophagy, or “self-eating”, a cell extends a de novo generated double membrane around selectively recruited cytoplasmic content. The cytoplasmic contents are enclosed in the newly formed autophagosome. Subsequent fusion with lysosomes leads to degradation of autophagosome contents which can include organelles, macromolecular complexes and soluble cytoplasmic proteins.
Autophagy allows cells to adapt to a variety of stresses and constitutes a line of defence against many intracellular bacteria and viruses. Autophagy is deficient in many tumors and neurodegenerative diseases and fundamentally contributes to their progression. As a consequence, mTOR inhibitors, which activate autophagy are currently one of the most investigated classes of therapeutics for cancer and neurodegenerative diseases.
Degradation of
Our recent studies have uncovered two mechanisms by which autophagy controls RNA complexes. First, we discovered a multi-layered regulation of key RNA silencing proteins by autophagy that impacts miRNA function (Gibbings et al., Nature Cell Biology, 2012). Our latest published research shows that autophagy degrades the RNA intermediate of retrotransposons, or jumping genes, to slow their ability to mutate the genome (Guo et al., Nature Communications, 2014). Retrotransposons play critical roles in the evolution of species and are increasingly appreciated to be a major cause of genetic mutation in cancer, the brain and perhaps other tissues. Currently, we are working to systematically identify RNAs degraded by autophagy as well as addressing the role of RNA degradation by autophagy in diseases from Amyotrophic Lateral Sclerosis, cancer and neurodegenerative diseases.
Over the past 20 years researchers have carefully investigated the proteins and organelles degraded by autophagy. In contrast, which RNAs are degraded by autophagy and the consequences of this for cancer, motor neuron and neurodegenerative diseases has been largely neglected. Recent technical innovations now allow us to identify RNAs degraded by autophagy and discover how this major substrate of autophagy contributes to disease.