Intraflagellar transport
Encyclopedia
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 discovered 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.
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 flagellum.
The IFT particles themselves consist of two sub-complexes, each made up of several individual IFT protein
s. 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:
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.
s 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, liver disease
, primary ciliary dyskinesia
, nephronophthisis
, Alstrom 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.
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
.
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
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 discovered in 1993 by graduate student Keith Kozminski while working in the lab of Dr. Joel Rosenbaum
Joel Rosenbaum
Joel Rosenbaum is a professor of cell biology at Yale University .Rosenbaum received his bachelor's degree from Syracuse University in 1955, and later his M.Sc. Ed. from St. Lawrence University in 1957. He returned later to Syracuse for his Masters in 1959 and Ph.D...
at Yale University
Yale University
Yale University is a private, Ivy League university located in New Haven, Connecticut, United States. Founded in 1701 in the Colony of Connecticut, the university is the third-oldest institution of higher education in the United States...
. The process of IFT has been best characterized in the biflagellate alga Chlamydomonas reinhardtii
Chlamydomonas reinhardtii
Chlamydomonas reinhardtii is a single celled green alga about 10 micrometres in diameter that swims with two flagella. They have a cell wall made of hydroxyproline-rich glycoproteins, a large cup-shaped chloroplast, a large pyrenoid, and an "eyespot" that senses light.Although widely distributed...
as well as the sensory cilia of the nematode
Nematode
The nematodes or roundworms are the most diverse phylum of pseudocoelomates, and one of the most diverse of all animals. Nematode species are very difficult to distinguish; over 28,000 have been described, of which over 16,000 are parasitic. It has been estimated that the total number of nematode...
Caenorhabditis elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
.
It has been suggested based on localization studies that IFT proteins also function outside of cilia.
Biochemistry
Axoneme
Numerous eukaryotic cells carry whip-like appendages whose inner core consists of a cytoskeletal structure called the axoneme....
, between the axoneme and the plasma membrane. Studies have shown that the movement of IFT particles along the microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
is carried out by two different microtubule-based motors; the anterograde (towards the flagellar tip) motor is kinesin
Kinesin
A kinesin is a protein belonging to a class of motor proteins found in eukaryotic cells. Kinesins move along microtubule filaments, and are powered by the hydrolysis of ATP . The active movement of kinesins supports several cellular functions including mitosis, meiosis and transport of cellular...
-2, and the retrograde (towards the cell body) motor is cytoplasmic dynein
Dynein
Dynein is a motor protein in cells which converts the chemical energy contained in ATP into the mechanical energy of movement. Dynein transports various cellular cargo by "walking" along cytoskeletal microtubules towards the minus-end of the microtubule, which is usually oriented towards the cell...
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 protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s. 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, and IFT122
- complex B contains IFT172, IFT88IFT88Intraflagellar transport protein 88 homolog is a protein that in humans is encoded by the IFT88 gene.-Further reading:...
, IFT81IFT81Intraflagellar transport protein 81 homolog is a protein that in humans is encoded by the IFT81 gene. Together with IFT74/72 it forms a core complex to build IFT particles which are required for cilium formation. Additionally, it interacts with basal body components as CEP170 which regulates the...
, IFT80IFT80Intraflagellar transport protein 80 homolog , also known as WD repeat-containing protein 56, is a protein that in humans is encoded by the IFT80 gene.- Function :...
, IFT74IFT74Intraflagellar transport protein 74 homolog , also known as coiled-coil domain-containing protein 2 and capillary morphogenesis gene 1 protein , is a protein that in humans is encoded by the IFT74 gene....
, IFT57IFT57Intraflagellar transport protein 57 homolog is a protein that in humans is encoded by the IFT57 gene.-Interactions:IFT57 has been shown to interact with Caspase 8.-Further reading:...
, IFT52, IFT46, IFT27, and IFT20IFT20Intraflagellar transport protein 20 homolog is a protein that in humans is encoded by the IFT20 gene. The gene is composed of 6 exons and islocated on human chromosome 17p11.1...
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
CEP170
Centrosomal protein 170kDa, also known as CEP170, is a protein that in humans is encoded by the CEP170 gene.- Function :The product of this gene is a component of the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells...
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 phenotypePhenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
s 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
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
polycystic kidney disease
Polycystic kidney disease
Autosomal dominant polycystic kidney disease is an inherited systemic disorder that predominantly affects the kidneys, but may affect other organs including the liver, pancreas, brain, and arterial blood vessels...
model phenotype in mice. Other human diseases such as retinal degeneration
Retinal degeneration
The term retinal degeneration may refer to:* One of several eye diseases or eye disorders in humans* Progressive retinal atrophy, an eye disease in dogs-See also:*List of human eye diseases and disorders...
, situs inversus
Situs inversus
Situs inversus is a congenital condition in which the major visceral organs are reversed or mirrored from their normal positions. The normal arrangement is known as situs solitus...
(a reversal of the body's left-right axis), Senior-Loken syndrome, liver disease
Polycystic liver disease
Polycystic liver disease usually describes the presence of multiple cysts scattered throughout normal liver tissue, in association with polycystic kidney disease.-Pathophysiology:Associations with PRKCSH and SEC63 have been described....
, primary ciliary dyskinesia
Primary ciliary dyskinesia
Primary ciliary dyskinesia , also known as immotile ciliary syndrome or Kartagener Syndrome ', is a rare, ciliopathic, autosomal recessive genetic disorder that causes a defect in the action of the cilia lining the respiratory tract and fallopian tube, and also of the flagella of sperm in...
, nephronophthisis
Nephronophthisis
Nephronophthisis is a genetic disorder of the kidneys which affects children. It is classified as a medullary cystic kidney disease.The disorder is inherited in an autosomal recessive fashion and, although rare, is the most common genetic cause of childhood kidney failure.It is a form of...
, Alstrom syndrome
Alstrom syndrome
Alström syndrome is a rare genetic disorder caused by mutations in the gene ALMS1. It is among the rarest genetic disorders in the world, as currently it has only 266 reported cases in medical literature and over 501 known cases in 47 countries. It was first described by Carl-Henry Alström in...
, Meckel-Gruber syndrome, Sensenbrenner syndrome
Sensenbrenner syndrome
Sensenbrenner syndrome is a rare multisystem disease first described in 1975. It is inherited in an autosomal recessive fashion, and a number of genes appear to be responsible...
, Jeune syndrome, and Bardet-Biedl syndrome
Bardet-Biedl syndrome
The Bardet–Biedl syndrome is a ciliopathic human genetic disorder that produces many effects and affects many body systems. It is characterized principally by obesity, retinitis pigmentosa, polydactyly, mental retardation, hypogonadism, and renal failure in some cases.-Summary of the...
, which causes both cystic kidneys and retinal degeneration, have been linked to the IFT machinery. This diverse group of genetic syndromes
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
and genetic diseases
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
are now understood to arise due to malfunctioning cilia, and the term "ciliopathy
Ciliopathy
A ciliopathy is a genetic disorder of the cellular cilia or the cilia anchoring structures, the basal bodies, or of ciliary function.Although ciliopathies are usually considered to involve proteins that localize to the primary cilia or centrosomes, it is possible for ciliopathies to be associated...
" is now used to indicate their common origin.
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 signaling pathways. Specifically, IFT has been implicated as a mediator of Sonic Hedgehog
Sonic hedgehog
Sonic hedgehog homolog is one of three proteins in the mammalian signaling pathway family called hedgehog, the others being desert hedgehog and Indian hedgehog . SHH is the best studied ligand of the hedgehog signaling pathway. It plays a key role in regulating vertebrate organogenesis, such as...
signaling, one of the most important pathways in embryogenesis
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
.
External links
- For a time-lapse microscopic Quicktime movie and schematic cartoon of IFT, see Rosenbaum Lab IFT webpage.