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Intraflagellar transport

{{Short description|Cellular process}}

File:IFTcilia.jpg]]

Intraflagellar transport (IFT) is a bidirectional motility along axoneme microtubules that is essential for the formation (ciliogenesis) and maintenance of most eukaryotic cilia and flagella.{{cite web |url=http://www.pandasthumb.org/archives/2007/06/of_cilia_and_si.html |title=The Panda's Thumb: Of cilia and silliness (More on Behe) |website=www.pandasthumb.org |access-date=13 January 2022 |archive-url=https://web.archive.org/web/20070914042614/http://www.pandasthumb.org/archives/2007/06/of_cilia_and_si.html |archive-date=14 September 2007 |url-status=dead}} 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.{{cite journal | pmid = 9585417 | doi=10.1083/jcb.141.4.993 | pmc=2132775 | volume=141 | issue=4 | title=Chlamydomonas kinesin-II-dependent intraflagellar transport (IFT): IFT particles contain proteins required for ciliary assembly in Caenorhabditis elegans sensory neurons | date=May 1998 | journal=J. Cell Biol. | pages=993–1008 | last1 = Cole | first1 = DG | last2 = Diener | first2 = DR | last3 = Himelblau | first3 = AL | last4 = Beech | first4 = PL | last5 = Fuster | first5 = JC | last6 = Rosenbaum | first6 = JL}}

IFT was first reported in 1993 by graduate student Keith Kozminski while working in the lab of Dr. Joel Rosenbaum at Yale University.{{Cite journal | last1 = Bhogaraju | first1 = S. | last2 = Taschner | first2 = M. | last3 = Morawetz | first3 = M. | last4 = Basquin | first4 = C. | last5 = Lorentzen | first5 = E. | title = Crystal structure of the intraflagellar transport complex 25/27 | journal = The EMBO Journal | volume = 30 | issue = 10 | pages = 1907–1918 | year = 2011 | pmid = 21505417 | pmc = 3098482 | doi = 10.1038/emboj.2011.110}}{{cite journal|last=Kozminski|first=KG|author2=Johnson KA |author3=Forscher P |author4=Rosenbaum JL. |title=A motility in the eukaryotic flagellum unrelated to flagellar beating|journal=Proc Natl Acad Sci U S A|year=1993|volume=90|issue=12|pages=5519–23|pmid=8516294|doi=10.1073/pnas.90.12.5519|pmc=46752|bibcode=1993PNAS...90.5519K|doi-access=free}} 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.{{cite journal|last=Orozco|first=JT|author2=Wedaman KP |author3=Signor D |author4=Brown H |author5=Rose L |author6=Scholey JM |title=Movement of motor and cargo along cilia|journal=Nature|year=1999|volume=398|pages=674|pmid=10227290|doi=10.1038/19448|issue=6729|bibcode=1999Natur.398..674O|s2cid=4414550|doi-access=free}}

It has been suggested based on localization studies that IFT proteins also function outside of cilia.{{cite journal |vauthors=Sedmak T, Wolfrum U |title=Intraflagellar transport molecules in ciliary and nonciliary cells of the retina |journal=J. Cell Biol. |volume=189 |issue=1 |pages=171–86 |date=April 2010 |pmid=20368623 |pmc=2854383 |doi=10.1083/jcb.200911095 }}

Biochemistry

{{See also|Axonal transport}}

Image:IFTsimplified.JPG

Intraflagellar transport (IFT) describes the bi-directional movement of non-membrane-bound particles along the doublet microtubules of the flagellar, and motile cilia 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 motors; the anterograde (towards the flagellar tip) motor is heterotrimeric 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 flagellum.{{cite journal|last=Rosenbaum|first=JL|author2=Witman GB|title=Intraflagellar Transport|journal=Nat Rev Mol Cell Biol|year=2002|volume=3|issue=11|pages=813–25|pmid=12415299|doi=10.1038/nrm952|s2cid=12130216}}{{cite journal|last=Scholey|first=JM|title=Intraflagellar transport motors in cilia: moving along the cell's antenna|journal=Journal of Cell Biology|year=2008|volume=180|pages=23–29|pmid=18180368|doi=10.1083/jcb.200709133|issue=1|pmc=2213603}}

The IFT particles themselves consist of two sub-complexes,{{cite journal |vauthors=Lucker BF, Behal RH, Qin H, etal |title=Characterization of the intraflagellar transport complex B core: direct interaction of the IFT81 and IFT74/72 subunits |journal=J. Biol. Chem. |volume=280 |issue=30 |pages=27688–96 |date=July 2005 |pmid=15955805 |doi=10.1074/jbc.M505062200 |doi-access=free }} 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, IFT140, IFT139, IFT122, IFT121 and IFT43{{cite journal|author=Behal RH1, Miller MS, Qin H, Lucker BF, Jones A, Cole DG.|title=Subunit interactions and organization of the Chlamydomonas reinhardtii intraflagellar transport complex A proteins|journal=J. Biol. Chem.|year=2012 |volume=287|pages=11689–703|pmid=22170070|doi=10.1074/jbc.M111.287102|issue=15|pmc=3320918|doi-access=free}}
  • complex B contains IFT172, IFT88, IFT81, IFT80, IFT74, IFT57, IFT56,{{Cite journal |last1=Xin |first1=Daisy |last2=Christopher |first2=Kasey J. |last3=Zeng |first3=Lewie |last4=Kong |first4=Yong |last5=Weatherbee |first5=Scott D. |date=2017-04-15 |title=IFT56 regulates vertebrate developmental patterning by maintaining IFTB complex integrity and ciliary microtubule architecture |url=https://journals.biologists.com/dev/article/144/8/1544/48404/IFT56-regulates-vertebrate-developmental |journal=Development |language=en |volume=144 |issue=8 |pages=1544–1553 |doi=10.1242/dev.143255 |pmid=28264835 |pmc=5399663 |issn=1477-9129}} IFT54,{{Cite journal |last1=Taschner |first1=Michael |last2=Weber |first2=Kristina |last3=Mourão |first3=André |last4=Vetter |first4=Melanie |last5=Awasthi |first5=Mayanka |last6=Stiegler |first6=Marc |last7=Bhogaraju |first7=Sagar |last8=Lorentzen |first8=Esben |date=April 2016 |title=Intraflagellar transport proteins 172, 80, 57, 54, 38, and 20 form a stable tubulin-binding IFT -B2 complex |url=https://www.embopress.org/doi/10.15252/embj.201593164 |journal=The EMBO Journal |language=en |volume=35 |issue=7 |pages=773–790 |doi=10.15252/embj.201593164 |pmid=26912722 |issn=0261-4189|pmc=4818760 }} IFT52, IFT46, IFT38, IFT27, IFT25,{{Cite journal |last1=Wang |first1=Zhaohui |last2=Fan |first2=Zhen-Chuan |last3=Williamson |first3=Shana M. |last4=Qin |first4=Hongmin |date=2009-05-01 |editor-last=Jin |editor-first=Dong-Yan |title=Intraflagellar Transport (IFT) Protein IFT25 Is a Phosphoprotein Component of IFT Complex B and Physically Interacts with IFT27 in Chlamydomonas |journal=PLOS ONE |language=en |volume=4 |issue=5 |pages=e5384 |doi=10.1371/journal.pone.0005384 |doi-access=free |pmid=19412537 |bibcode=2009PLoSO...4.5384W |issn=1932-6203|hdl=1969.1/182092 |hdl-access=free }} IFT22,{{Cite journal |last1=Wachter |first1=Stefanie |last2=Jung |first2=Jamin |last3=Shafiq |first3=Shahaan |last4=Basquin |first4=Jerome |last5=Fort |first5=Cécile |last6=Bastin |first6=Philippe |last7=Lorentzen |first7=Esben |date=2019-05-02 |title=Binding of IFT22 to the intraflagellar transport complex is essential for flagellum assembly |url=https://www.embopress.org/doi/10.15252/embj.2018101251 |journal=The EMBO Journal |language=en |volume=38 |issue=9 |doi=10.15252/embj.2018101251 |issn=0261-4189|pmc=6484408 }} and IFT20

IFT-B complex have been further subcategorized to IFT-B1 (core) and IFT-B2 (peripheral) subcomplexes. These subcomplexes were first described by Lucker et al. in an experiment on Chlamydomonas reinhardtii, using increased ionic strength to dissociate the peripheral particles from the whole IFT-B complex. They realized that the core particles do not need the peripheral ones in order to form an assembly.{{Cite journal |last1=Lucker |first1=Ben F. |last2=Behal |first2=Robert H. |last3=Qin |first3=Hongmin |last4=Siron |first4=Laura C. |last5=Taggart |first5=W. David |last6=Rosenbaum |first6=Joel L. |last7=Cole |first7=Douglas G. |date=July 2005 |title=Characterization of the Intraflagellar Transport Complex B Core |journal=Journal of Biological Chemistry |language=en |volume=280 |issue=30 |pages=27688–27696 |doi=10.1074/jbc.M505062200|doi-access=free |pmid=15955805 }}

  • IFT-B1 (core) consists of IFT172, IFT80, IFT 57, IFT54, IFT38, IFT20 (six members).{{Cite journal |last1=Takei |first1=Ryota |last2=Katoh |first2=Yohei |last3=Nakayama |first3=Kazuhisa |date=2018-01-01 |title=Robust interaction of IFT70 with IFT52–IFT88 in the IFT-B complex is required for ciliogenesis |journal=Biology Open |volume=7 |issue=5 |language=en |doi=10.1242/bio.033241 |pmid=29654116 |pmc=5992529 |issn=2046-6390}}
  • IFT-B2 (peripheral) consists of IFT88, IFT81, IFT74, IFT70, IFT56, IFT52, IFT46, IFT27, IFT25, IFT22 (10 members).

The biochemical properties and biological functions of 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.{{cite thesis |author=Lamla S |title=Functional characterisation of the centrosomal protein Cep170 |year=2009 |work=Dissertation |publisher=LMU Muenchen: Fakultät für Biologie |url=http://edoc.ub.uni-muenchen.de/9783/|type=Text.PhDThesis }}

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 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.{{cite journal | vauthors = Shohayeb, B, et al. | title = The association of microcephaly protein WDR62 with CPAP/IFT88 is required for cilia formation and neocortical development | journal = Hum. Mol. Genet. | volume = 29 | issue = 2 | pages = 248–263 |date=December 2020 | doi = 10.1093/hmg/ddz281 | pmid = 31816041 | doi-access = free }} Other human diseases such as retinal degeneration, situs inversus (a reversal of the body's left-right axis), 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.{{cite journal

| last = Badano

| first = Jose L.

|author2=Norimasa Mitsuma |author3=Phil L. Beales |author4=Nicholas Katsanis

| title = The Ciliopathies : An Emerging Class of Human Genetic Disorders

| journal = Annual Review of Genomics and Human Genetics

| volume = 7

| pages = 125–148

| date = September 2006

| doi = 10.1146/annurev.genom.7.080505.115610

| pmid = 16722803}} These and possibly many more disorders may be better understood via study of IFT.

class="wikitable"

|+Human genetic syndromes associated with mutations in IFT genes

IFT geneOther nameHuman diseasereference
IFT27RABL4Bardet–Biedl syndrome{{cite journal |author=Aldahmesh, M. A., Li, Y., Alhashem, A., Anazi, S., Alkuraya, H., Hashem, M., Awaji, A. A., Sogaty, S., Alkharashi, A., Alzahrani, S., Al Hazzaa, S. A., Xiong, Y., Kong, S., Sun, Z., Alkuraya, F. S. |title=IFT27, encoding a small GTPase component of IFT particles, is mutated in a consanguineous family with Bardet-Biedl syndrome.|journal=Hum. Mol. Genet. |volume= 23 |issue=12|pages=3307–3315 |date=2014 |pmid= 24488770 |doi=10.1093/hmg/ddu044 |pmc=4047285}}
IFT43C14ORF179Sensenbrenner syndrome{{cite journal |author=Arts, H. H., Bongers, E. M. H. F., Mans, D. A., van Beersum, S. E. C., Oud, M. M., Bolat, E., Spruijt, L., Cornelissen, E. A. M., Schuurs-Hoeijmakers, J. H. M., de Leeuw, N., Cormier-Daire, V., Brunner, H. G., Knoers, N. V. A. M., Roepman, R. |title=C14ORF179 encoding IFT43 is mutated in Sensenbrenner syndrome.|journal=J. Med. Genet. |volume= 48|issue=6|pages=390–395 |date=2011 |pmid= 21378380 |doi=10.1136/jmg.2011.088864|s2cid=6073572|url=https://hal.archives-ouvertes.fr/hal-00613258/document}}
IFT121WDR35Sensenbrenner syndrome{{cite journal |author=Gilissen, C., Arts, H. H., Hoischen, A., Spruijt, L., Mans, D. A., Arts, P., van Lier, B., Steehouwer, M., van Reeuwijk, J., Kant, S. G., Roepman, R., Knoers, N. V. A. M., Veltman, J. A., Brunner, H. G. |title=Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome.|journal=Am. J. Hum. Genet. |volume= 87 |issue=3|pages=418–423 |date=2010 |pmid= 20817137 |doi=10.1016/j.ajhg.2010.08.004 |pmc=2933349}}
IFT122WDR10Sensenbrenner syndrome{{cite journal |author=Walczak-Sztulpa, J., Eggenschwiler, J., Osborn, D., Brown, D. A., Emma, F., Klingenberg, C., Hennekam, R. C., Torre, G., Garshasbi, M., Tzschach, A., Szczepanska, M., Krawczynski, M., Zachwieja, J., Zwolinska, D., Beales, P. L., Ropers, H.-H., Latos-Bielenska, A., Kuss, A. W. |title=Cranioectodermal dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene.|journal=Am. J. Hum. Genet. |volume= 86 |issue=6|pages=949–956 |date=2010 |pmid= 20493458 |doi=10.1016/j.ajhg.2010.04.012 |pmc=3032067}}
IFT140KIAA0590Mainzer–Saldino syndrome{{cite journal |author=Perrault, I., Saunier, S., Hanein, S., Filhol, E., Bizet, A. A., Collins, F., Salih, M. A. M., Gerber, S., Delphin, N., Bigot, K., Orssaud, C., Silva, E., and 18 others. |title=Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations.|journal=Am. J. Hum. Genet. |volume= 90 |issue=5|pages=864–870 |date=2012 |pmid= 22503633 |doi=10.1016/j.ajhg.2012.03.006 |pmc=3376548}}
IFT144WDR19Jeune syndrome, Sensenbrenner syndrome{{cite journal |author=Bredrup, C., Saunier, S., Oud, M. M., Fiskerstrand, T., Hoischen, A., Brackman, D., Leh, S. M., Midtbo, M., Filhol, E., Bole-Feysot, C., Nitschke, P., Gilissen, C., and 16 others. |title=Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19.|journal=Am. J. Hum. Genet. |volume= 89 |issue=5|pages=634–643 |date=2011 |pmid= 22019273 |doi=10.1016/j.ajhg.2011.10.001 |pmc=3213394}}
IFT172SLBJeune syndrome, Mainzer–Saldino syndrome{{cite journal |author=Halbritter, J., Bizet, A. A., Schmidts, M., Porath, J. D., Braun, D. A., Gee, H. Y., McInerney-Leo, A. M., Krug, P., Filhol, E., Davis, E. E., Airik, R., Czarnecki, P. G., and 38 others. |title=Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans.|journal=Am. J. Hum. Genet. |volume= 93 |issue=5|pages=915–925 |date=2013 |pmid= 24140113 |doi=10.1016/j.ajhg.2013.09.012 |pmc=3824130}}

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,{{cite journal |vauthors=Eggenschwiler JT, Anderson KV |title=Cilia and developmental signaling|journal=Annu Rev Cell Dev Biol |volume=23 |pages=345–73 |date=January 2007 |pmid= 17506691 |doi=10.1146/annurev.cellbio.23.090506.123249 |pmc=2094042}} one of the most important pathways in embryogenesis.

References

{{Reflist|30em}}

Further reading

  • {{cite journal |vauthors=Orozco JT, Wedaman KP, Signor D, Brown H, Rose L, Scholey JM |title=Movement of motor and cargo along cilia |journal=Nature |volume=398 |issue=6729 |pages=674 |date=April 1999 |pmid=10227290 |doi=10.1038/19448|bibcode=1999Natur.398..674O |s2cid=4414550 |doi-access=free }}
  • {{cite journal |doi=10.1083/jcb.141.4.993 |vauthors=Cole DG, Diener DR, Himelblau AL, Beech PL, Fuster JC, Rosenbaum JL |title=Chlamydomonas kinesin-II-dependent intraflagellar transport (IFT): IFT particles contain proteins required for ciliary assembly in Caenorhabditis elegans sensory neurons |journal=J. Cell Biol. |volume=141 |issue=4 |pages=993–1008 |date=May 1998 |pmid=9585417 |pmc=2132775 }}
  • {{cite journal |vauthors=Pan X, Ou G, Civelekoglu-Scholey G, etal |title=Mechanism of transport of IFT particles in C. elegans cilia by the concerted action of kinesin-II and OSM-3 motors |journal=J. Cell Biol. |volume=174 |issue=7 |pages=1035–45 |date=September 2006 |pmid=17000880 |pmc=2064394 |doi=10.1083/jcb.200606003 }}
  • {{cite journal |vauthors=Qin H, Burnette DT, Bae YK, Forscher P, Barr MM, Rosenbaum JL |title=Intraflagellar transport is required for the vectorial movement of TRPV channels in the ciliary membrane |journal=Curr. Biol. |volume=15 |issue=18 |pages=1695–9 |date=September 2005 |pmid=16169494 |doi=10.1016/j.cub.2005.08.047 |s2cid=15658145 |doi-access=free |bibcode=2005CBio...15.1695Q }}
  • {{cite journal |vauthors=Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, Yoder BK |title=Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function |journal=PLOS Genet. |volume=1 |issue=4 |pages=e53 |date=October 2005 |pmid=16254602 |pmc=1270009 |doi=10.1371/journal.pgen.0010053 |doi-access=free }}
  • {{cite journal |vauthors=Briggs LJ, Davidge JA, Wickstead B, Ginger ML, Gull K |title=More than one way to build a flagellum: comparative genomics of parasitic protozoa |journal=Curr. Biol. |volume=14 |issue=15 |pages=R611–2 |date=August 2004 |pmid=15296774 |doi=10.1016/j.cub.2004.07.041 |s2cid=42754598 |url=https://ora.ox.ac.uk/objects/uuid:cae9e25a-5d18-469e-bb1e-4e4581d1467b |doi-access=free |bibcode=2004CBio...14.R611B }}

External links

  • For a time-lapse microscopic QuickTime movie and schematic cartoon of IFT, see [https://web.archive.org/web/20090418220756/http://www.yale.edu/rosenbaum/images_videos.html Rosenbaum Lab IFT webpage].

{{Ciliary proteins}}

{{DEFAULTSORT:Intraflagellar Transport}}

Category:Cellular processes