The Intraflagellar Transport Machinery

Abstract

Eukaryotic cilia and flagella are evolutionarily conserved organelles that protrude from the cell surface. The unique location and properties of cilia allow them to function in vital processes such as motility and signaling. Ciliary assembly and maintenance rely on intraflagellar transport (IFT), the bidirectional movement of a multicomponent transport system between the ciliary base and tip. Since its initial discovery more than two decades ago, considerable effort has been invested in dissecting the molecular mechanisms of IFT in a variety of model organisms. Importantly, IFT was shown to be essential for mammalian development, and defects in this process cause a number of human pathologies known as ciliopathies. Here, we review current knowledge of IFT with a particular emphasis on the IFT machinery and specific mechanisms of ciliary cargo recognition and transport.

Figure 1.

Schematic overview of the main steps during intraflagellar transport (IFT). Because of important differences in various organisms (mainly regarding IFT motors), the individual steps are shown for both Chlamydomonas reinhardtii (top; only one anterograde motor) and Caenorhabditis elegans (bottom; two anterograde motors). (Top) (1) In C. reinhardtii, IFT trains are assembled from IFT-A and IFT-B particles at the ciliary base around the transition fibers and bind to the anterograde motor, the retrograde motor (as a cargo), soluble and membrane cargos, as well as the BBSome. (2) The trains enter the cilium, and (3) move processively toward the ciliary tip (anterograde IFT). (4) At the tip, the IFT trains are remodeled, cargo is unloaded, and the anterograde motor is inactivated (by phosphorylation). (5) The inactive heterotrimeric kinesin 2 motor exits the flagellum independently of retrograde IFT. (6) Retrograde IFT trains assemble at the ciliary tip with active IFT dynein linking them to the ciliary axoneme. (7) Processive retrograde IFT returns the trains and associated proteins back to the ciliary base, and (8) the trains exit flagella and get disassembled. (Bottom) (1) In C. elegans, IFT-A and IFT-B particles also form trains at the ciliary base, and this step is assisted by the BBSome complex. (2) After binding to cargos (retrograde motor, soluble cargos, membrane cargos, BBSome), the heterotrimeric kinesin 2 motor transports the trains through the transition zone (characterized by Y-shaped connectors linking the microtubule (MT) doublets to the ciliary membrane). (3) Along the ciliary proximal segment (“handover zone”) heterotrimeric kinesin 2 gradually dissociates from the trains and is replaced by homodimeric kinesin 2 (OSM-3). (4) Along the ciliary distal segment, the trains are exclusively moved by OSM-3. (5) At the tip the trains are remodeled, cargo is unloaded, and the anterograde motor is inactivated. (6) Retrograde trains assemble, which contain activated IFT dynein and inactivated OSM-3 as a retrograde cargo. (7) Retrograde IFT returns the trains back to the ciliary base. (8) Along the proximal segment, OSM-3 is gradually unloaded, and (9) inactive heterotrimeric kinesin 2 is picked up for transport back to the base. (10) Trains exit the cilium and are disassembled. TF, Transition fiber; BB, basal body.

Figure 2.

Interactions within intraflagellar transport (IFT) proteins and interaction between IFT proteins/complexes and ciliary motor/cargo proteins (see text for details). MT, Microtubule; C. reinhardtii, Chlamydomonas reinhardtii; C. elegans, Caenorhabditis elegans.