Cystoproteins are the product of genes that are mutated in cystic diseases of the kidney in humans, mice and zebrafish. They are expressed in primary cilia, basal bodies or centrosomes.
Many cystoproteins localize to more than one intracellular domain. Depending on the cell-cycle stage, some of them localize to adherens junctions or focal adhesions. The arrow within the primary cilium indicates the direction of anterograde transport along the microtubule system, which is mediated by kinesin II, a heterotrimeric protein that consists of two motor units (KIF3A and KIF3B, kinesin family members 3A and 3B) and one non-motor unit (KAP3, kinesin-associated protein 3).
Cystoproteins are highly conserved in evolution and are expressed in many organ systems, which account for CDK-associated pleiotropic phenotypes, such as retinitis pigmentosa, anosmia, ataxia, liver fibrosis, situs inversus, cardiac defects, infertility and obesity.
Evolutionary conservation
Given the central role of cilia in many biological processes and their involvement in CDK it is not surprising that many of the proteins that are involved in the CDK phenotypes of vertebrates have been conserved over more than 1.5 109 years of evolution from C. reinhardtii to vertebrates.
Mutations in many cystoprotein-coding genes lead to a conserved renal cystic phenotype among vertebrates. For example, mutations in inversin lead to CDK in humans, mice and zebrafish.
In addition, expression patterns and phenotypes that are associated with CDK in vertebrates seem to be conserved in Caenorhabditis elegans: many orthologues of mammalian cystoproteins are expressed in head (amphid) and tail (phasmid) neurons, which are osmosensor ciliated neurons of C. elegans.
This includes the PKD1 orthologue lov-1, as well as pkd-2, nph-1, nph-4, and many BBS orthologues79, 80. Knockdown of nph-1 and nph-4 leads to a phenotype of impaired male mating79 that is similar to the phenotype that has been described for lov-1 and pkd-2 mutants.
Consistent with a role of the BBS proteins in centrosome-basal body organization and ciliary function, translational Bbs-Gfp fusion transgenes for bbs-1, bbs-2, bbs-7 and bbs-8 are seen at the ciliary transition zones of basal bodies and axonems.
BBS-GFP fusion proteins undergo intraflagellar transport (IFT), and loss of function of bbs-7 and bbs-8 leads to shortened cilia and defective IFT of some IFT proteins.
This phenotype seems to be highly conserved in evolution, as defects of cystoprotein orthologues in C. reinhardtii have deficient IFT and flagellar propulsion82, and C. elegans bbs-7 and bbs-8 are required for the correct localization and motility of the IFT proteins OSM-5/polaris and CHE-11 (the human orthologue of which is the hypothetical gene product KIAA0590).
A better understanding of IFT in C. reinhardtii should lead to insights into disease mechanisms of CDK in vertebrates.
Domains
Some of the cystoprotein domains are shared between different proteins. Coiled-coil domains, for example, occur in 6 out of 7 proteins that are defective in NPHP-like diseases (nephrocystin-1, -2, -3 and -5, OFD1, and ALMS1).
Certain protein domains are relevant to ciliary function, (such as the PilF (pilus formation) domain1) and show evolutionary conservation with even the prokaryotes.
References
Hildebrandt F, Otto E. Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease? Nat Rev Genet. 2005 Dec;6(12):928-40. PMID: 16341073