Research

Eukaryotes have developed signaling networks that control transcription, translation, and protein modification to adapt to changing environmental conditions. At times of shortage, cells need to save energy and nutrients by maintaining basal and essential activities. Autophagy lies at a fundamental junction in cell fate, determining death or survival. The integration between stress-induced pathways and autophagic proteins is rather complex, given that different cues are funneled to activate a relatively small pool of autophagic proteins.

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Autophagosome biogenesis

The mechanism of autophagosome biogenesis is still elusive. Our knowledge concerning the order of incorporation of the different factors into sites of autophagosome formation, as well as on the functional complexes involved in this process, has increased substantially in recent years. However, the exact details concerning the way in which all of these factors act in concert are still missing. The reconstitution of such a step in the test tube will clearly be very challenging, but if successful it will provide invaluable information on this process.

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Selective autophagy

Targeting of cytosolic proteins for lysosomal degradation via the autophagic pathway in the mammalian system was long considered to be a nonselective process. This view changed with the identification of the ubiquitin-binding proteins that specifically interact with mammalian Atg8s. We have studied the crucial role Atg8s play a in selective cargo recruitment into autophagosomes, a process mediated by their interaction with p62 and NBR1, two scaffold proteins that interact with ubiquitinated protein aggregates. We are currently studying the mechanism by which specific cargo molecules are recruited into autophagosomes under different physiological conditions.

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Autophagy in cancer and neurodegeneration

Autophagy is implicated in adaptive response of cells to provide nutrients and energy upon exposure to stress conditions. Cancer cells are known to undergo various forms of stress, including oncogenic (Ras signaling), metabolic (hypoxia and starvation), and therapeutic (drug treatment) stress, and are dependent on autophagy to clear damaged structures, and to restore metabolic and homeostatic balance. Inhibition of autophagy by siRNA and lysosomal inhibitors (e.g. hydroxychloroquine) has been associated with anti-tumor activities in preclinical models and in the clinic. We are currently engaged in developing tools to selectively regulate autophagy in cancer cells.

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