HGNC Approved Gene Symbol: TTLL11
Cytogenetic location: 9q33.2 Genomic coordinates (GRCh38): 9:121,815,674-122,093,308 (from NCBI)
TTLL11 is a tubulin glutamylase that catalyzes posttranslational polyglutamylation of microtubules (MTs). TTLL11 functions against the MT deglutamylase CCPP1 (AGTPBP1; 606830) to fine-tune MT glutamylation, which has implications in many biologic processes, including ciliary function and chromosome segregation (O'Hagan et al., 2017, Zadra et al., 2022).
O'Hagan et al. (2017) identified C. elegans Ttll11. C. elegans Ttll11 encodes 2 isoforms, Ttll11b and Ttll11a, which contain 707 and 607 amino acids, respectively, which are identical except for a 100-amino acid N-terminal extension in Ttll11b. Ttll11B contains a putative myristoylation sequence at its N terminus. Both Ttll11b and Ttll11a share significant amino acid homology with the human TTLL11 long isoform. Reporter analysis showed that Ttll11b was expressed exclusively in ciliated extracellular vesicle (EV)-releasing neurons in C. elegans, whereas Ttll11a was expressed in a distinct and nonoverlapping set of ciliated sensory neurons. In C. elegans EV neurons, Ttll11 localized in puncta throughout sensory neurons, including axons, cell bodies, and dendrites, and was enriched in cilia.
By database analysis, Zadra et al. (2022) found that TTLL11 was widely expressed in human tissues. Immunofluorescence assays revealed that fluorescent-tagged TTLL11 localized to the spindle during mitosis of HeLa cells.
Gross (2024) mapped the TTLL11 gene to chromosome 9q33.2 based on an alignment of the TTLL11 sequence (GenBank AF521886) with the genomic sequence (GRCh38).
O'Hagan et al. (2017) identified Ttll11 as a tubulin glutamylase that opposed the tubulin deglutamylase activity of Ccpp1 in EV-releasing neurons of C. elegans. Consistent with their expression patterns, Ttll11b was an EV neuron-specific glutamylase, whereas Ttll11a functioned in a distinct and nonoverlapping set of neurons. Ttll11 was essential for glutamylation of ciliary MTs and was involved in regulation of both initiation and elongation of glutamate side chains. By working with Ccpp1, Tttll11 regulated ciliary function by controlling ciliary receptor localization, the velocity of particular kinesin motors, the release of extracellular vesicles, and sculpting of a specialized axonemal ultrastructure. The opposing functions of Ttll11 and Ccpp1 fine-tuned ciliary MT glutamylation to regulate ciliary transport, EVs, and axonemal structure in C. elegans.
Using a forward genetic screen, Power et al. (2020) identified Ttll11 as a gene whose mutation suppressed hyperglutamylation and progressive degeneration of neuronal cilia in C. elegans with a Ccpp1 mutation. Immunofluorescence assays showed that Ttll11 activity was essential for MT glutamylation in C. elegans, especially for adding the initiating glutamate side chains, but not for ciliogenesis. Further analysis indicated that Ttll11 mutation suppressed the defective phenotypes of C. elegans with Ccpp1 mutation by suppressing the heterotrimeric kinesin II (see 604683) span shortening.
By knockdown analysis in HeLa cells, Zadra et al. (2022) showed that TTLL11 posttranslationally polyglutamylated spindle MTs, with a preference for glutamate side chain elongation, during mitosis. Analysis of TTLL11 downregulation in HeLa cells and zebrafish embryos revealed that MT polyglutamylation by TTLL11 was required for chromosome segregation fidelity and, thus, for error-free mitosis. Database analysis showed that TTLL11 expression was downregulated in cancer, and TTLL11 downregulation correlated with reduction of polyglutamylation of spindle MTs. Moreover, TTLL11 downregulation was part of a cancer signature likely caused by overexpression of the oncogenes CCNE1 (123837) or CDC25A (116947) as part of a tumor-specific transcriptional program. MT polyglutamylation defined the dynamic properties of spindle MTs, as spindle MTs were partially stabilized in the absence of TTLL11, suggesting that MT polyglutamylation likely fine-tuned spindle MT dynamics to ensure faithful chromosome segregation.
Gross, M. B. Personal Communication. Baltimore, Md. 1/30/2024.
O'Hagan, R., Silva, M., Nguyen, K. C. Q., Zhang, W., Bellotti, S., Ramadan, Y. H., Hall, D. H., Barr, M. M. Glutamylation regulates transport, specializes function, and sculpts the structure of cilia. Curr. Biol. 27: 3430-3441, 2017. [PubMed: 29129530] [Full Text: https://doi.org/10.1016/j.cub.2017.09.066]
Power, K. M., Akella, J. S., Gu, A., Walsh, J. D., Bellotti, S., Morash, M., Zhang, W., Ramadan, Y. H., Ross, N., Golden, A., Smith, H. E., Barr, M. M., O'Hagan, R. Mutation of NEKL-4/NEK10 and TTLL genes suppress neuronal ciliary degeneration caused by loss of CCPP-1 deglutamylase function. PLoS Genet. 16: e1009052, 2020. [PubMed: 33064774] [Full Text: https://doi.org/10.1371/journal.pgen.1009052]
Zadra, I., Jimenez-Delgado, S., Anglada-Girotto, M., Segura-Morales, C., Compton, Z. J., Janke, C., Serrano, L., Ruprecht, V., Vernos, I. Chromosome segregation fidelity requires microtubule polyglutamylation by the cancer downregulated enzyme TTLL11. Nature Commun. 13: 7147, 2022. [PubMed: 36414642] [Full Text: https://doi.org/10.1038/s41467-022-34909-y]