TY - JOUR
T1 - The tubulin deglutamylase CCPP-1 regulates the function and stability of sensory cilia in C. elegans
AU - O'Hagan, Robert
AU - Piasecki, Brian P.
AU - Silva, Malan
AU - Phirke, Prasad
AU - Nguyen, Ken C.Q.
AU - Hall, David H.
AU - Swoboda, Peter
AU - Barr, Maureen M.
N1 - Funding Information:
This work was supported by the National Institutes of Health (NIH) NRSA 5F32NS56540-4 and NJCSCR 10-2951-SCR-E-0 fellowships to R.O.; a Fulbright Fellowship and a Lars Hiertas Minne Foundation grant to B.P.P.; NIH RO1DK059418 grant to M.M.B.; grants from the Swedish Research Council, Marcus Borgström Foundation, and the NordForsk Nordic Networks for C. elegans and Cilia and Centrosome Research to P.S.; NIH RR12596 grant to D.H.H.; and Einstein funds for access to the New York Structural Biology Center (NYSBC). We thank Bill Rice and KD Derr (NYSBC) for help in using the Technai20 microscope and creating electron tomograms. Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources, The C. elegans Gene Knockout Consortium, and the National Bioresource Project for the Nematode (Japan). Thanks to the Drummond and Gorovsky laboratories for the anti-polyglycylation antibodies. We also thank Natalia Morsci, Andrew Jauregui, and Julie Maguire for plasmids and strains and members of the Barr laboratory for discussions and constructive criticism of this manuscript.
PY - 2011/10/25
Y1 - 2011/10/25
N2 - Background: Posttranslational modifications (PTMs) such as acetylation, detyrosination, and polyglutamylation have long been considered markers of stable microtubules and have recently been proposed to guide molecular motors to specific subcellular destinations. Microtubules can be deglutamylated by the cytosolic carboxypeptidase CCP1. Loss of CCP1 in mice causes cerebellar Purkinje cell degeneration. Cilia, which are conserved organelles that play important diverse roles in animal development and sensation, contain axonemes comprising microtubules that are especially prone to PTMs. Results: Here, we report that a CCP1 homolog, CCPP-1, regulates the ciliary localization of the kinesin-3 KLP-6 and the polycystin PKD-2 in male-specific sensory neurons in C. elegans. In male-specific CEM (cephalic sensilla, male) cilia, ccpp-1 also controls the velocity of the kinesin-2 OSM-3/KIF17 without affecting the transport of kinesin-II cargo. In the core ciliated nervous system of both males and hermaphrodites, loss of ccpp-1 causes progressive defects in amphid and phasmid sensory cilia, suggesting that CCPP-1 activity is required for ciliary maintenance but not ciliogenesis. Affected cilia exhibit defective B-tubules. Loss of TTLL-4, a polyglutamylating enzyme of the tubulin tyrosine ligase-like family, suppresses progressive ciliary defects in ccpp-1 mutants. Conclusions: Our studies suggest that CCPP-1 acts as a tubulin deglutamylase that regulates the localization and velocity of kinesin motors and the structural integrity of microtubules in sensory cilia of a multicellular, living animal. We propose that the neuronal degeneration caused by loss of CCP1 in mammals may represent a novel ciliopathy in which cilia are formed but not maintained, depriving the cell of cilia-based signal transduction.
AB - Background: Posttranslational modifications (PTMs) such as acetylation, detyrosination, and polyglutamylation have long been considered markers of stable microtubules and have recently been proposed to guide molecular motors to specific subcellular destinations. Microtubules can be deglutamylated by the cytosolic carboxypeptidase CCP1. Loss of CCP1 in mice causes cerebellar Purkinje cell degeneration. Cilia, which are conserved organelles that play important diverse roles in animal development and sensation, contain axonemes comprising microtubules that are especially prone to PTMs. Results: Here, we report that a CCP1 homolog, CCPP-1, regulates the ciliary localization of the kinesin-3 KLP-6 and the polycystin PKD-2 in male-specific sensory neurons in C. elegans. In male-specific CEM (cephalic sensilla, male) cilia, ccpp-1 also controls the velocity of the kinesin-2 OSM-3/KIF17 without affecting the transport of kinesin-II cargo. In the core ciliated nervous system of both males and hermaphrodites, loss of ccpp-1 causes progressive defects in amphid and phasmid sensory cilia, suggesting that CCPP-1 activity is required for ciliary maintenance but not ciliogenesis. Affected cilia exhibit defective B-tubules. Loss of TTLL-4, a polyglutamylating enzyme of the tubulin tyrosine ligase-like family, suppresses progressive ciliary defects in ccpp-1 mutants. Conclusions: Our studies suggest that CCPP-1 acts as a tubulin deglutamylase that regulates the localization and velocity of kinesin motors and the structural integrity of microtubules in sensory cilia of a multicellular, living animal. We propose that the neuronal degeneration caused by loss of CCP1 in mammals may represent a novel ciliopathy in which cilia are formed but not maintained, depriving the cell of cilia-based signal transduction.
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U2 - 10.1016/j.cub.2011.08.049
DO - 10.1016/j.cub.2011.08.049
M3 - Article
C2 - 21982591
AN - SCOPUS:80054995650
SN - 0960-9822
VL - 21
SP - 1685
EP - 1694
JO - Current Biology
JF - Current Biology
IS - 20
ER -