Intraflagellar transport


Intraflagellar transport or IFT is a bidirectional motility along axonemal microtubules that is essential for the formation and maintenance of most eukaryotic cilia and flagella. It is thought to be required to build all cilia that assemble within a membrane projection from the cell surface. Plasmodium falciparum cilia and the sperm flagella of Drosophila are examples of cilia that assemble in the cytoplasm and do not require IFT. The process of IFT involves movement of large protein complexes called IFT particles or trains from the cell body to the ciliary tip and followed by their return to the cell body. The outward or anterograde movement is powered by kinesin-2 while the inward or retrograde movement is powered by cytoplasmic dynein 2/1b. The IFT particles are composed of about 20 proteins organized in two subcomplexes called complex A and B.
IFT was first reported in 1993 by graduate student Keith Kozminski while working in the lab of Dr. Joel Rosenbaum at Yale University. The process of IFT has been best characterized in the biflagellate alga Chlamydomonas reinhardtii as well as the sensory cilia of the nematode Caenorhabditis elegans.
It has been suggested based on localization studies that IFT proteins also function outside of cilia.

Biochemistry

IFT describes the bi-directional movement of non-membrane-bound particles along the doublet microtubules of the flagellar axoneme, between the axoneme and the plasma membrane. Studies have shown that the movement of IFT particles along the microtubule is carried out by two different microtubule-based motors; the anterograde motor is heterotrimeric kinesin-2, and the retrograde motor is cytoplasmic dynein 1b. IFT particles carry axonemal subunits to the site of assembly at the tip of the axoneme; thus, IFT is necessary for axonemal growth. Therefore, since the axoneme needs a continually fresh supply of proteins, an axoneme with defective IFT machinery will slowly shrink in the absence of replacement protein subunits. In healthy flagella, IFT particles reverse direction at the tip of the axoneme, and are thought to carry used proteins, or "turnover products," back to the base of the flagellum.
The IFT particles themselves consist of two sub-complexes, each made up of several individual IFT proteins. The two complexes, known as 'A' and 'B,' are separable via sucrose centrifugation. The many subunits of the IFT complexes have been named according to their molecular weights:
The biochemical properties and biological functions of these IFT subunits are just beginning to be elucidated, for example they interact with components of the basal body like CEP170 or proteins which are required for cilium formation like tubulin chaperone and membrane proteins.

Physiological importance

Due to the importance of IFT in maintaining functional cilia, defective IFT machinery has now been implicated in many disease phenotypes generally associated with non-functional cilia. IFT88, for example, encodes a protein also known as Tg737 or Polaris in mouse and human, and the loss of this protein has been found to cause an autosomal-recessive polycystic kidney disease model phenotype in mice. Further, the mislocalization of this protein following WDR62 knockdown in mice results in brain malformation and ciliopathies. Other human diseases such as retinal degeneration, situs inversus, Senior–Løken syndrome, liver disease, primary ciliary dyskinesia, nephronophthisis, Alström syndrome, Meckel–Gruber syndrome, Sensenbrenner syndrome, Jeune syndrome, and Bardet–Biedl syndrome, which causes both cystic kidneys and retinal degeneration, have been linked to the IFT machinery. This diverse group of genetic syndromes and genetic diseases are now understood to arise due to malfunctioning cilia, and the term "ciliopathy" is now used to indicate their common origin.
These and possibly many more disorders may be better understood via study of IFT.
IFT geneOther nameHuman diseasereference
IFT27RABL4Bardet–Biedl syndrome
IFT43C14ORF179Sensenbrenner syndrome
IFT121WDR35Sensenbrenner syndrome
IFT122WDR10Sensenbrenner syndrome
IFT140KIAA0590Mainzer–Saldino syndrome
IFT144WDR19Jeune syndrome, Sensenbrenner syndrome
IFT172SLBJeune syndrome, Mainzer–Saldino syndrome

One of the most recent discoveries regarding IFT is its potential role in signal transduction. IFT has been shown to be necessary for the movement of other signaling proteins within the cilia, and therefore may play a role in many different signaling pathways. Specifically, IFT has been implicated as a mediator of sonic hedgehog signaling, one of the most important pathways in embryogenesis.