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J. Biol. Chem., Vol. 281, Issue 41, 30707-30716, October 13, 2006

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TTLL7 Is a Mammalian -Tubulin Polyglutamylase Required for Growth of MAP2-positive Neurites^*

Koji Ikegami, Masahiro Mukai, Jun-ichi Tsuchida, Robb L. Heier^¶, Grant R. MacGregor^¶, and Mitsutoshi Setou^||**1

From the Mitsubishi Kagaku Institute of Life Sciences, Minamiooya, Machida, Tokyo 194-8511, Japan, ^||PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama, Japan, the ^**National Institute for Physiological Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan, the Mitsubishi Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan, and the ^¶Department of Developmental and Cell Biology, Developmental Biology Center, and Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, California 92697-3940

Microtubules form a cytoskeletal framework that influences cell shape and provides structural support for the cell. Microtubules in the nervous system undergo a unique post-translational modification, polyglutamylation of the C termini of their tubulin subunits. The mammalian enzymes that perform -tubulin polyglutamylation as well as their physiological functions in the neuronal tissue remain elusive. We report identification of a mammalian polyglutamylase with specificity for -tubulin as well as its distribution and function in neurite growth. To identify putative tubulin polyglutamylases, we searched tubulin tyrosine ligase-like (TTLL) proteins for those predominantly expressed in the nervous system. Of 13 TTLL proteins, TTLL7 was transcribed at the highest level in the nervous system. Recombinant TTLL7 catalyzed tubulin polyglutamylation with high preference to -tubulin in vitro. When expressed in HEK293T cells, TTLL7 demonstrated specificity for -tubulin and not for -tubulin or nucleosome assembly protein 1. Consistent with these findings, knockdown of TTLL7 in a primary culture of superior cervical ganglion neurons caused a loss of polyglutamylated -tubulin. Following stimulation of PC12 cells with nerve growth factor to differentiate, the level of TTLL7 increased concomitantly with polyglutamylation of -tubulin. Short interference RNA-mediated knockdown of TTLL7 repressed nerve growth factor-stimulated MAP (microtubule-associated protein) 2-positive neurite growth in PC12 cells. Consistent with having a role in the growth of MAP2-positive neurites, TTLL7 accumulated within a MAP2-enriched somatodendritic portion of superior cervical ganglion, as did polyglutamylated -tubulin. Anti-TTLL7 antibody revealed that TTLL7 was distributed in a somatodendritic compartment in the mouse brain. These findings indicate that TTLL7 is a -tubulin polyglutamylase and is required for the growth of MAP2-positive neurites in PC12 cells.

Received for publication, April 26, 2006 , and in revised form, July 26, 2006.

^* This work was supported by a WAKATE-B grant from the Japan Society for the Promotion of Science (to K. I.), a grant from the National Institutes of Health (to G. R. M.), PRESTO and SENTAN grants from the Japan Science and Technology Agency (to M. S.), and a WAKATE-A grant from the Japan Society for the Promotion of Science (to M. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and Table S1.

¹ To whom correspondence should be addressed: National Institute for Physiological Science, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan. Tel.: 81-42-724-6259; Fax: 81-42-724-6341; E-mail: setou{at}nips.ac.jp.

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