The OFD1 protein is a novel player in selective autophagy: another tile to the cilia/autophagy puzzle.

The autophagy-lysosomal pathway is one of the main degradative routes which cells use to balance sources of energy. A number of proteins orchestrate the formation of autophagosomes, membranous organelles instrumental in autophagy. Selective autophagy, involving the recognition and removal of specific targets, is mediated by autophagy receptors, which recognize cargos and the autophagosomal membrane protein LC3 for lysosomal degradation. Recently, bidirectional crosstalk has emerged between autophagy and primary cilia, microtubule-based sensory organelles extending from cells and anchored by the basal body, derived from the mother centriole of the centrosome. The molecular mechanisms underlying the direct role of autophagic proteins in cilia biology and, conversely, the impact of this organelle in autophagy remains elusive. Recently, we uncovered the molecular mechanism by which the centrosomal/basal body protein OFD1 controls the LC3-mediated autophagic cascade. In particular, we demonstrated that OFD1 acts as a selective autophagy receptor by regulating the turnover of unc-51-like kinase (ULK1) complex, which plays a crucial role in the initiation steps of autophagosome biogenesis. Moreover, we showed that patients with a genetic condition caused by mutations in OFD1 and associated with cilia dysfunction, display excessive autophagy and we demonstrated that autophagy inhibition significantly ameliorates the renal cystic phenotype in a conditional mouse model recapitulating the features of the disease (Morleo et al. 2020, EMBO J, doi: 10.15252/embj.2020105120). We speculate that abnormal autophagy may underlie some of the clinical manifestations observed in the disorders ascribed to cilia dysfunction.