THE OFD1 PROTEIN CONTROLS AUTOPHAGOSOME BIOGENESIS THROUGH SELECTIVE AUTOPHAGY

Cilia are cellular projections that serve a wide variety of essential functions in mammals. Defects in cilia structure or function have emerged as etiological mechanisms underpinning human diseases called ciliopathies. The OFD1 gene, defective in a rare developmental ciliopathy known as Oral facial digital syndrome type I, encodes for a centrosomal/basal body protein required for cilia formation. Recent data link ciliary structures to autophagy, the major intracellular degradation system, although the mechanisms and the main players underlying this connection are still to be determined. Autophagy is an evolutionarily conserved and strictly regulated lysosomal pathway which plays a wide variety of physiological and pathophysiological roles in cellular homeostasis. Either too little or too much autophagy may contribute to pathological conditions. In the past decade a great deal of progress has been made in the molecular dissection of stimulatory autophagy inputs. On the other hand, our understanding of the mechanisms that restrain autophagy is only partial and far from being complete. Data obtained during my PhD program contribute to the description of a new negative feedback mechanism that inhibits autophagosome biogenesis through selective autophagy-mediated degradation of ATG13, a component of the ULK1 autophagy initiation complex. I demonstrate that the ciliary OFD1 protein is involved in selective autophagy and acts as autophagy receptor for ATG13 via direct interaction with the Atg8/LC3/GABARAP family of proteins. Preliminary data also indicate that excessive autophagy may contribute to the disease pathogenesis. My results add a new tile to the puzzle of the cilia/autophagy interconnection and will help shedding light on these complex biological processes.