The Tubulin Deglutamylase CCPP-1 Regulates the Function and Stability of Sensory Cilia in C. elegans

Abstract

Summary Background Post-translational 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 comprised of 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, 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.

Intracellular cargo transport by kinesin-3 motors

“…In line with this idea, knockdown of polyglutamylase PGs1 in ROSA22 mice decreases the localization of KIF1A to neurites [103]. Further, the ciliary localization of kinesin 3 KLP 6 in C. elegans is positively regulated by tubulin deglutamylase CCPP 1 [104]. However, in COS cells, the truncated, constitutively active KIF1A(1 393) was a non selective motor [105].…”

Tubulin detyrosination promotes monolayer formation and apical trafficking in epithelial cells

“…In this present report we demonstrate that apical trafficking of soluble, raftassociated or non-associated cargo proteins can be modulated by TTL expression and alterations in intracellular detyr-tubulin, which suggests that stable detyrosinated microtubules serve as tracks for kinesin-driven post Golgi transport to the apical membrane domain of MDCK cells, especially considering that kinesin motors do not move preferentially along dynamic microtubules (Cai et al, 2009). Recent data on the function and stability of sensory cilia in C. elegans support the idea of posttranslationally modified microtubules that guide molecular motors to specific subcellular destinations (O'Hagan et al, 2011). The authors propose that these tubulin modifications regulate the velocity of kinesin-2 motors.…”

Cytosolic Carboxypeptidase 1 Is Involved in Processing α- and β-Tubulin

“…Disruption of tubulin dynamics can cause mitochondrial dysfunction and lead to neurodegeneration (52). Recently, using Caenorhabditis elegans as an animal model, it was shown that tubulin deglutamylation by CCP1 regulates localization and activity of molecular motors in cilia (53). Changes in tubulin processing can potentially explain the myriad defects found in pcd mice, including abnormal accumulation of polysomes (9), altered transcription and DNA repair (10,11), endoplasmic reticulum stress (12), formation of axonal spheroids (13), mitochondrial dysfunction (14), elevated autophagy (15), and abnormal dendritic development (16).…”