Abstract

Cilia are cell-surface organelles essential for sensory perception, intercellular signaling, cell locomotion, and fluid flow generation. Proper maintenance of the ciliary proteome, including removal of damaged or mislocalized proteins as well as achieving the correct stoichiometry of signaling components, is fundamental for these processes. Imbalances in this maintenance are associated with a range of human ciliopathies including polycystic kidney disease, retinal degeneration, and developmental disorders such as Bardet-Biedl and Joubert syndromes. The temporospatial distribution of proteins within cilia is regulated by intraflagellar transport (IFT), wherein molecular trains shuttle between the cell body and cilium. I will describe our efforts to structurally characterize the components of IFT trains using single-particle cryo-EM. I will also describe a newly identified coincidence detection mechanism that allows ubiquitinated proteins to be recognized and removed from cilia. These findings advance our understanding of ubiquitin-mediated protein transport and ciliary proteostasis, and demonstrate how structural changes in IFT trains achieve cargo selectivity.