Intraflagellar transport

Intraflagellar Transport or IFT refers to the cellular process essential for the formation and maintenance of eukaryotic cilia and flagella. IFT, first discovered in 1993 by graduate student Keith Kozminski while working in the lab of Dr. Joel Rosenbaum [1] at Yale University, is phylogenically well-conserved, and it seems to be present in the cilia and flagella of most species, with Plasmodium falciparum being a notable exception.[2] 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.

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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 (towards the flagellar tip) motor is kinesin-2, and the retrograde (towards the cell body) 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 organelle. For a time-lapse microscopic Quicktime movie and schematic cartoon of IFT, see "Rosenbaum Lab IFT webpage" [3]

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 (both complexes at approximately 16S, but under increased ionic strength complex B sediments more slowly, thus segregating the two complexes). The many subunits of the IFT complexes have been named according to their molecular weights; complex A contains IFT144, 140, 139, and 122, while complex B contains IFT 172, 88, 81, 80, 74/72, 57/55, 52, 46, 27, and 20. The biochemical properties and biological functions of these IFT subunits are just beginning to be elucidated.

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 (or absent) cilia. IFT88, for example, encodes a protein known as Tg737 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. Other human diseases such as retinal degeneration, situs inversus (a reversal of the body's left-right axis), Senior-Loken syndrome, Jeune syndrome, and Bardet-Biedl syndrome, which causes both cystic kidneys and retinal degeneration, have been linked to the IFT machinery. These and possibly many more disorders may be better understood via study of IFT.

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 signalling pathways. Specifically, IFT has been implicated as a mediator of Sonic Hedgehog signaling, one of the most important pathways in embryonic development.

References

"Intraflagellar Transport"; Joel L. Rosenbaum and George B. Witman, Nature Reviews, 2002 Entrez PubMed 12415299

"Movement of Motor and Cargo along Cilia"; Jose T. Orozco et al, Nature, 1999, Vol 398, page 674 Entrez PubMed 10227290

"Chlamydomonas Kinesin-II-dependent Intraflagellar Transport (IFT): IFT Particles Contain Proteins Required for Ciliary Assembly in Caenorhabditis elegans Sensory Neurons"; Douglas G. Cole et al, The Journal of Cell Biology, 1998 Entrez PubMed 9585417

"Mechanism of transport of IFT particles in C. elegans cilia by the concerted action of kinesin-II and OSM-3 motors"; Xiaoyu Pan et al, The Journal of Cell Biology, Vol 174, page 1035, 2006 Entrez PubMed 17000880

"Intraflagellar Transport is Required for the Vectorial Movement of TRPV Channels in the Ciliary Membrane"; Hongmin Qin et al, Current Biology, 2005 Entrez PubMed 16169494

"Gli2 and Gli3 Localize to Cilia and Require the Intraflagellar Transport Protein Polaris for Processing and Function"; Courtney J. Haycraft et al, 2005 Entrez PubMed 16254602

"More than one way to build a flagellum: comparative genomics of parasitic protozoa." Current Biology, Volume 14, Issue 15, Pages R611-R612; L. Briggs, J. Davidge, B. Wickstead, M. Ginger, K. Gull