Functional segregation and emerging role of cilia‐related cytosolic carboxypeptidases (CCPs)

Abstract

Recent experimental data indicating axonal regeneration, axogenesis, dendritogenesis, and ciliary axoneme assembly and wellness have linked the role of cytosolic metallocarboxypeptidase 1 (CCP1/AGTPBP1/Nna1) to the microtubule network. In addition, 5 of the 6 mammalian ccp genes have been shown to participate in post-translational modifications of tubulin, which occur in the microtubules of neurons, mitotic spindles, cilia, and basal bodies. Here, we compile evidence for the idea that the occurrence of CCPs strongly correlates with the presence of cilia, suggesting that CCP functions might be primarily related to cilia and basal bodies (CBBs). In agreement with this hypothesis, CCPs were localized in centrioles, basal bodies, and mitotic spindles in HeLa cells by confocal microscopy. By reconstructing the evolutionary history of CCPs, we show their presence in the last eukaryotic common ancestor and relate each group of CCP orthologs to specific roles in CBBs. The clues presented in this study suggest that during the evolution of eukaryotes, mechanisms mediated by CCPs through tubulin post-translational modifications controlling assembly, trafficking, and signaling in the microtubules, were transferred from cilia to cell and axon microtubules.

Glutamylation Regulates Transport, Specializes Function, and Sculpts the Structure of Cilia

“…Examples of hyperglutamylation leading to disease include mutations in the deglutamylase AGBL5, associated with retinal degeneration in humans [54], and loss of the deglutamylase Ccp1, which causes progressive neurodegeneration and sperm immotility in mice [20]. A growing list of reports links hypoglutamylation to disease.…”

“…Joubert syndrome [17], blindness [18], and schizophrenia [19], are associated with defects in TTLL glutamylases. Defects in the Ccp1 deglutamylase cause neuronal degeneration in mice [20]. How dysregulated glutamylation might contribute to human disease is largely unknown.…”

Zebrafish Cytosolic Carboxypeptidases 1 and 5 Are Essential for Embryonic Development

“…It may be that CCP2 plays a more important role in the adult. Recently, it has been shown in HeLa cells that CCP2 colocalizes with ␥-tubulin within centrioles and with polyglutamylated tubulin within the basal bodies of primary cilia (34). One study suggested that CCP2 functions as a tubulin tyrosine carboxypeptidase (24).…”

“…They showed that loss of CCPP-6 gene function resulted in increased polyglutamylation, whereas overexpression resulted in decreased polyglutamylation. In cultured HeLa cells, CCP6 has been found to colocalize with centrioles and basal bodies (34).…”

“…Based on localization to the developing olfactory placode and previously reported roles for CCP family members in tubulin processing and ciliary function (12,13,15,34), the olfactory placode was examined by confocal microscopy using acetylated tubulin and polyglutamate antibodies to identify the tubulinrich ciliated cells of the olfactory placode (35,36). Both the acetylated tubulin and polyglutamate antibodies showed robust immunofluorescent staining of the olfactory placode.…”