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Role of the tubulin posttranslational modifications and microtubule severing protein, katanin in the cilia central pair assembly

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Katanin in cilia

Cilia are microtubule-based cell protrusions with sensory and locomotory functions. Katanin, the microtubule severing protein and changes in the level of tubulin posttranslational modifications affect assembly of proper cilia structure and may represent the underlying cause in ciliary genetic disorders.

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Cilia are evolutionary conserved microtubule-based cell protrusions. There are two types of cilia: motile cilia and non-motile or primary cilia, which serve as sensory organelles. In humans, primary cilia are found on nearly every cell in the body. The microtubule skeleton of cilia is composed of nine doublets of peripheral microtubules. Motile cilia consist of two additional central microtubules, so-called central pair (CP). Earlier observations indicated that lack or mutation of microtubule severing protein p60 katanin or its regulatory subunit, p80, leads to formation of cilia that lack CP microtubules. The EU-funded CP ASSEMBLY IN CILIA (Role of the tubulin posttranslational modifications and microtubule severing protein, katanin in the cilia central pair assembly) project was initiated to investigate the role of the microtubule severing protein, katanin and tubulin modifications in the assembly of CP microtubules. Researchers analysed p60 and p80 katanin subunits in Tetrahymena cells and showed that molecular mechanisms that regulate katanin level and activity are evolutionary conserved. In depth domain analysis of katanin subunits showed that the N-terminal fragment of KAT1p, a p60 ortholog, is sufficient to associate with microtubules and that this association is enhanced if both katanin subunit are expressed. The prolonged overexpression of KAT3p, a Tetrahymena ortholog of p80, results in inhibition of cytokinesis leading to formation of multinuclear monster cells similar as in KAT1 knockouts. Moreover overexpression of only KAT3p fragment containing WD40 motifs is sufficient to phenocopy KAT1-KO. The in vitro assay showed that microtubules from alpha tubulin acetyltransferase overexpressing cells were fragmented slightly faster than from wild type cells. The elevated level of tubulin acetylation had no effect on katanin localization. However, in cells with hyperglutamylated microtubules the p60 ortholog KAT1p was depleted from cilia and basal bodies while localization of the p80 ortholog, KAT3p was not affected. Researchers found also that in Tetrahymena cells the level of katanin subunits is regulated by 26S-dependent protein degradation. Researchers investigated also the role of katanin p60 homolog, KATNAL2 and showed that in Tetrahymena cells KATNAL2 ortholog, KAT2p is a ciliary protein that co-localizes mainly with peripheral microtubules but also with central microtubules. These fundamental studies highlighted the importance of katanin in proper cilia assembly and function. Results of the CP ASSEMBLY IN CILIA project helped scientists to understand the basis of some cilia-related syndromes and diseases.


Cilia, microtubules, genetic disorders, katanin, CP ASSEMBLY IN CILIA

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