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Tubulin glycylases are required for primary cilia, control of cell proliferation and tumor development in colon

Authors:
Cecilia Rocha
Cecilia Rocha
Cecilia Rocha
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Laura Papon at Institute of Molecular Genetics of Montpellier, French National Centre for Scientific Research
Laura Papon
Wulfran Cacheux
Wulfran Cacheux
Wulfran Cacheux
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Patricia Marques Sousa
Patricia Marques Sousa
Patricia Marques Sousa
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Abstract

TTLL3 and TTLL8 are tubulin glycine ligases catalyzing posttranslational glycylation of microtubules. We show here for the first time that these enzymes are required for robust formation of primary cilia. We further discover the existence of primary cilia in colon and demonstrate that TTLL3 is the only glycylase in this organ. As a consequence, colon epithelium shows a reduced number of primary cilia accompanied by an increased rate of cell division in TTLL3-knockout mice. Strikingly, higher proliferation is compensated by faster tissue turnover in normal colon. In a mouse model for tumorigenesis, lack of TTLL3 strongly promotes tumor development. We further demonstrate that decreased levels of TTLL3 expression are linked to the development of human colorectal carcinomas. Thus, we have uncovered a novel role for tubulin glycylation in primary cilia maintenance, which controls cell proliferation of colon epithelial cells and plays an essential role in colon cancer development.
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Corrigendum
Tubulin glycylases are required for primary cilia,
control of cell proliferation and tumor development
in colon
Cecilia Rocha, Laura Papon, Wulfran Cacheux, Patricia Marques Sousa, Valeria Lascano, Olivia Tort,
Tiziana Giordano, Sophie Vacher, Benedicte Lemmers, Pascale Mariani, Didier Meseure, Jan Paul
Medema, Ivan Bièche, Michael Hahne & Carsten Janke
DOI 10.15252/embj.201490279
Correction to: The EMBO Journal (2014) 33: 2247–2260. DOI 10.15252/embj.201488466 | Published online 01 September 2014
We stated in several places in our article that our work is the
first to describe glycylation in primary cilia. We realized that
this is not entirely correct since a previous publication
reported on the use of the glycylation-specific antibody TAP952
to recognize primary cilia (Davenport et al, 2007). This had
unfortunately escaped our attention, presumably due to the fact
that there is no comment on glycylated primary cilia in the
article text; TAP952 is only referred to as ‘ciliary marker’ in the
figure. We apologize for this oversight and any inconvenience
caused.
Reference
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Kesterson RA, Yoder BK (2007) Disruption of intraflagellar transport in
adult mice leads to obesity and slow-onset cystic kidney disease. Curr Biol
17:1586 –1594
ª2014 The Authors The EMBO Journal Vol 33 |No22 |2014 2735
Published online: November 18, 2014
... 43,44 TTLL3 has also been shown to be required for the formation of primary cilia, and loss of TTLL3 in colon epithelial cells resulted in increased cell proliferation and promoted the development of colon cancer in mouse models. 45 In contrast, our study found that increased TTLL8 expression was associated with a worse prognosis. Further studies are needed to elucidate the biological role of TTLL8 in ovarian cancer and understand why its expression may be associated with worse survival outcomes. ...
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... In ciliated cells such as those in the colon, post-translational modification of tubulin by glycylation regulates the length of primary cilia. In mammals, MT glycylation is catalyzed by tubulin tyrosine ligase-like (TTLL) glycyases, which control the proliferation of ciliated colon epithelial cells and play an essential role in the development of colon cancer [21]. Since IBD tissue injury, mucosal disruption, and symptomatic flare-ups are associated with oxidant-induced disruption of the cytoskeleton [22], we wished to determine the effect of DJ-X-013 treatment on the cytoskeleton in RAW 264.7 macrophages in a lipopolysaccharide (LPS)-induced model of inflammation. ...
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... Mice were injected intraperitoneally (i.p.) with AOM (6.25 mg per kg (body weight); 25843-45-2, Sigma-Aldrich), followed 30 days later by a single 5-day period of 2.5% (wt/vol) DSS (TdB) administered in the drinking water. Because TGFβR-KO mice did not regain weight after DSS treatment, no other induction of inflammation was performed, as is the case in the classical colitis-associated carcinogenesis protocol 54 . Mouse weight was measured every other day, and when an over 20% weight loss was observed, mice were killed. ...
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... Some of them are known to be linked with carcinogenesis. For example, tubulin glycine ligase TTLL3 knockdown decreased primary cilia and increased colon epithelial cell proliferation, promoting CRC development in mice and correlating with human CRC progression [37]. For other genes, such as VWA3A or EFHC1, we were unable to find significant confirmations in the literature. ...
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... In ciliated cells such as those in the colon, post-translational modification of tubulin by glycylation regulates the length of primary cilia. In mammals, MT glycylation is catalyzed by tubulin tyrosine ligase-like (TTLL) glycyases, which control the proliferation of ciliated colon epithelial cells and play an essential role in the development of colon cancer [21]. Since IBD tissue injury, mucosal disruption, and symptomatic flare-ups are associated with oxidant-induced disruption of the cytoskeleton [22], we wished to determine the effect of DJ-X-013 treatment on the cytoskeleton in RAW 264.7 macrophages in a lipopolysaccharide (LPS)-induced model of inflammation. ...
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Primary cilia and Gli3 activity regulate cerebral cortical size
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  • Sep 2012
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