InteractiveFly: GeneBrief

Cp110: Biological Overview | References

Gene name - Cp110

Synonyms -

Cytological map position - 20C1-20C1

Function - novel protein

Keywords - centriolar constituent, control of centriole length, suppression of centriole overduplication

Symbol - Cp110

FlyBase ID: FBgn0031191

Genetic map position - chrX:21884487-21887582

Classification - IQ motif, EF-hand binding site

Cellular location - centriolar component

NCBI link: EntrezGene

Cp110 orthologs: Biolitmine

CP110 is a centriole protein implicated in the regulation of cell division, centriole duplication, and centriole length and in the suppression of ciliogenesis. Surprisingly, this study reports that mutant flies lacking CP110 (CP110Δ) were viable and fertile and had no obvious defects in cell division, centriole duplication, or cilia formation. CP110 was shown to have at least three functions in flies. First, it subtly influences centriole length by counteracting the centriole-elongating activity of several centriole duplication proteins. Specifically, centrioles are ~10% longer than normal in CP110Delta mutants and ~20% shorter when CP110 is overexpressed. Second, CP110 ensures that the centriolar microtubules do not extend beyond the distal end of the centriole, as some centriolar microtubules can be more than 50 times longer than the centriole in the absence of CP110. Finally, and unexpectedly, CP110 suppresses centriole overduplication induced by the overexpression of centriole duplication proteins. These studies identify novel and surprising functions for CP110 in vivo in flies (Franz, 2013).

Centrioles are complex microtubule (MT)-based structures that guide the formation of two cell organelles -- the centrosome and the cilium. These organelles play an important part in various cell processes, and their dysfunction is linked to many human pathologies, including cancer, microcephaly, polycystic kidney disease, and obesity (Franz, 2013).

CP110 is a conserved centriolar protein that was first identified in mammalian cells as a Cdk substrate essential for centriole duplication (Chen, 2002). Subsequently, CP110 has been implicated in mitotic spindle assembly, cytokinesis, and the maintenance of genome stability (Tsang, 2006; D'Angiolella, 2010). In tissue culture cells, CP110 levels are tightly regulated during the cell cycle. CP110 is a major target of the SCFCyclin F ubiquitin ligase, and perturbing CP110 degradation leads to centrosome and spindle abnormalities and defects in chromosome segregation (D'Angiolella, 2010); the USP33 de-ubiquitinase appears to be essential for counteracting the activity of SCF in promoting CP110 destruction (Franz, 2013).

CP110 is concentrated at the distal end of centrioles, where it is required to suppress cilia formation (Spektor, 2007). When CP110, or its mammalian binding partner Cep97, are depleted from RPE-1 cells, the cells spontaneously form cilia when they would not normally do so, whereas overexpression of CP110 suppresses normal cilia formation. These findings suggest that CP110 normally suppresses cilia formation and that its removal from the distal end of centrioles is a prerequisite for cilia formation. In agreement with this, the conserved micro-RNA miR-129-3p regulates cilia biogenesis in cultured cells, at least in part, by down-regulating CP110, while Tau tubulin kinase 2 (TTBK2) initiates cilia formation, at least in part, by promoting the removal of CP110 from centrioles (Franz, 2013).

Recently, however, several groups reported that the depletion of CP110 in certain cultured mammalian cells does not lead to the ectopic formation of cilia, but rather to a dramatic elongation of the centrioles. This effect was similar to that seen when the centriole duplication protein CPAP/SAS-4 was overexpressed, suggesting that CP110 might antagonize the ability of CPAP/SAS-4 to promote centriole elongation. A possible explanation for the different results in different cell types is that CP110 suppresses ciliogenesis in cells that have the ability to form cilia (such as RPE-1 cells) and suppresses centriole elongation in cells that do not form cilia (such as U2OS cells) (Franz, 2013).

In human cells that can form cilia, CP110 has been shown to interact with the MT-depolymerizing kinesin Kif24C, and this kinesin can specifically remodel centriolar, but not cytoplasmic, MTs (Kobayashi, 2011). An interaction between CP110 and the MT-depolymerizing kinesin Klp10A was also reported in Drosophila S2 cells in culture (Delgehyr, 2012). Surprisingly, however, the depletion of CP110 in these cells leads to a shortening of the centrioles, suggesting that the loss of CP110 may have different consequences depending on the species and/or cell type (Franz, 2013).

Taken together, these observations suggest that CP110 has an important role in controlling the behavior of centrioles, centrosomes, and cilia; several mechanisms ensure the tight regulation of CP110 levels in cells, and there are severe consequences for the cell if this regulation is perturbed. A potential caveat to these studies, however, is that they were performed in cultured cells. A CP110-null mutation in Drosophila was generated in this study, allowing analysis cell behavior in the absence of this protein in vivo (Franz, 2013).

Previous studies in cultured cells have indicated that CP110 has important functions in promoting centriole duplication, cell cycle progression, cell division, regulating centriole length, and inhibiting cilia formation. Multiple mechanisms ensure that CP110 protein levels are tightly regulated in cells (D'Angiolella, 2010: Li, 2013). It is very surprising, therefore, that flies completely lacking CP110 are viable and fertile and that centriole duplication, cilia formation, cell division, and cell cycle progression are not dramatically perturbed. This study shows that Drosophila CP110 has at least three important functions in vivo: (1) it has a role in regulating centriole length although, under normal conditions, this role is subtle as centrioles are only slightly elongated in the absence of CP110, and slightly shortened when CP110 is overexpressed; (2) it has an important and previously undescribed role in ensuring that the centriolar MTs do not extend beyond the distal end of the centriole; and (3) surprisingly, it acts to suppress centriole overduplication when certain centriole duplication proteins are overexpressed (Franz, 2013).

In agreement with several previous studies in vertebrate cells in culture, the current results in vivo show that the depletion of CP110 in Drosophila leads to the inappropriate protrusion of MTs from the distal end of the centrioles. The vertebrate studies, however, concluded that these extensions were either elongated centrioles or cilia because several centriolar and/or ciliary proteins (depending on the cell type examined) were recruited to the protrusions. By contrast, the protrusions in Drosophila wing disc cells are clearly not cilia or elongated centrioles: they are largely composed of singlet MTs rather than the doublets found in most centrioles and cilia in flies, and they lack several proteins that centrioles normally contain. The reason(s) for this difference is unclear. Perhaps it simply reflects species differences: in Drosophila, the centrioles are usually composed of doublet MTs (rather than triplets), the central cartwheel usually extends throughout the length of both mother and daughter centrioles (rather than being largely confined to the proximal end of the daughter centriole), and mother centrioles lack visible distal appendages; thus, the effect of CP110 loss on the distal end of the centriole may be different in flies and vertebrates. Alternatively, perhaps CP110 is required to prevent the overgrowth of the centriolar MTs in flies and vertebrates, but some centriole/cilia proteins can bind to these abnormal MT extensions in vertebrates, but not in flies (Franz, 2013).

Moreover, in agreement with the vertebrate data, this study found that CP110 does play a part in regulating centriole length in flies; it is just that this role appears to be relatively minor: in wing disc cells lacking CP110, centrioles are only ~10% longer than those in WT cells, and in cells overexpressing CP110 they are ~20% shorter. We suspect that multiple mechanisms normally act to regulate centriole length in Drosophila cells in vivo, so perturbing any single mechanism may have only a subtle effect. Importantly, the function of CP110 in setting centriole length does not appear to require the second conserved region of CP110 (CR2), as the overexpression of either CP110S (which lacks CR2) or CP110L leads to centriole shortening. Thus, the data strongly suggest that CP110 has two separable functions in flies: 'capping' the length of the centriolar MTs, which only CP110L can perform, and helping to restrict centriole elongation, which can be performed by either CP110L or CP110S (Franz, 2013).

The findings suggest some interesting possibilities for how CP110 might perform these functions. It has previously been shown, for example, that CP110 interacts with the MT-depolymerizing kinesins Kif24A and Klp10A in human and fly cells, respectively (Kobayashi, 2011: Delgehyr, 2012). The idea that CP110 might recruit and/or regulate the MT-depolymerizing activity of Klp10A at the distal tip of centrioles is attractive. The 3D-SIM data suggest that CP110 is concentrated in a region just inside the distal end of the outer centriole wall. It is tempting to speculate that the interaction with CP110 might allow Klp10A to depolymerize any centriolar MTs that extend beyond the distal end of the centriole. Previous studies have shown that Klp10A can localize to the distal ends of centrioles (Delgehyr, 2012). A surprising point to emerge from the current studies is that in flies Klp10A appears to play a more important part than CP110 in preventing centriole over-elongation and centriolar MT overgrowth: both of these defects are more pronounced in Klp10A mutant cells than in cells completely lacking CP110 (in the latter case because primarily MT doublets elongate from Klp10A mutant centrioles, whereas primarily MT singlets elongate from CP110Δ centrioles) (Franz, 2013).

These results demonstrate that CP110 can regulate centriole length in flies by counteracting the length-promoting activity of certain core centriole duplication proteins. It has previously been shown in vertebrate-cultured cells that the overexpression of one such protein, CPAP/SAS-4, promotes centriole elongation in a similar manner to CP110 depletion. This study found that, in flies, overexpression of the core centriole duplication proteins DSas-4, DSas-6, or Ana2 can promote centriole elongation, but only if CP110 is absent. Thus, CP110 can counteract the centriole length-promoting activity of these proteins in vivo. Whether and how Klp10A might cooperate with CP110 to do this remains an interesting open question (Franz, 2013).

Surprisingly, it was also found that CP110 can counteract the ability of centriole duplication proteins, when overexpressed, to promote centriole overduplication. This was most unexpected because in cultured vertebrate cells CP110 is required for centriole overduplication. The reason for this discrepancy is unclear, although it is stressed that the current data demonstrate that CP110 is not normally required to regulate centriole duplication in flies in vivo; it only suppresses centriole overduplication when certain centriole duplication proteins are overexpressed. It is unclear how CP110 performs this function. One interesting possibility is that CP110 could suppress centriole overduplication in flies simply by preventing centriole over-elongation, as overly long centrioles can promote overduplication when extra daughter centrioles form along the extended centriole length. There is some evidence that argues against this idea: overexpressing DSas-4 in wing disc cells lacking CP110, for example, leads to centriole elongation but does not drive centriole overduplication in any of the tissues examined. An alternative possibility is suggested by the observation that a lack of CP110 leads to low levels of premature centriole separation in spermatocytes, which is often associated with centriole overduplication. It is interesting to note that the overexpression of different centriole duplication proteins induces centriole overduplication to different extents, and in slightly different ways, in different tissues both in the presence or absence of CP110. The reason for this is unclear, and more work is clearly required to analyze this phenomenon (Franz, 2013).

Although the mechanism by which CP110 suppresses centriole overduplication remains unclear, the observation that CP110 can protect cells from the damaging effects of centriole overduplication is potentially important. Although centrosome amplification per se does not seem to dramatically perturb cell physiology, at least in flies, centrosome amplification does predispose fly cells to form tumors and is a common feature of many cancer cells. The current data raise the possibility that the inactivation of CP110 might help promote centrosome amplification if the expression of certain key centriole duplication proteins is dysregulated (Franz, 2013).

Klp10A, a microtubule-depolymerizing kinesin-13, cooperates with CP110 to control Drosophila centriole length

Klp10A is a kinesin-13 of Drosophila melanogaster that depolymerizes cytoplasmic microtubules. In interphase, it promotes microtubule catastrophe; in mitosis, it contributes to anaphase chromosome movement by enabling tubulin flux. This study shows that Klp10A also acts as a microtubule depolymerase on centriolar microtubules to regulate centriole length. Thus, in both cultured cell lines and the testes, absence of Klp10A leads to longer centrioles that show incomplete 9-fold symmetry at their ends. These structures and associated pericentriolar material undergo fragmentation. It was also show that in contrast to mammalian cells, where depletion of CP110 leads to centriole elongation, in Drosophila cells it results in centriole length diminution that is overcome by codepletion of Klp10A to give longer centrioles than usual. How loss of centriole capping by CP110 might have different consequences for centriole length in mammalian and insect cells is discussed, and also these findings are related to the functional interactions between mammalian CP110 and another kinesin-13, Kif24, that in mammalian cells regulates cilium formation (Delgehyr, 2012).

To study Klp10A's roles at the spindle poles, flies with reduced Klp10A expression were examined that showed male sterility resulting from a P element insertion. Meiotic cells in Klp10A testes had supernumerary asters and abnormal, frequently multipolar meiotic spindles. Consistently, 79% of elongating spermatid bundles contained fewer than the normal 64 nuclei, and flagella were immotile and shorter than in control flies. Electron microscopy revealed that elongating spermatids had missing or incomplete axonemes. Moreover, Klp10A adults were uncoordinated and needed increased time to recover from mechanical shock, a hallmark of centriole defects (Delgehyr, 2012).

These findings led to an examination of centrioles in 16-cell cysts of primary spermatocytes in late G2 or in meiosis. Most such cells (>70%) were found to have more than two centrosomes together with additional rod- and dot-like structures that stained with anti-Dplp (Drosophila pericentrin-like protein). Moreover, whereas wild-type spermatocytes had only a few centrioles (2.2%) with no detectable Sas6 (spindle assembly abnormal protein 6) at their distal part, Klp10A spermatocytes showed an increase of such centrioles, suggesting they were incomplete or fragmented. Spd2 (spindle defective 2), which is closely associated with spermatocyte centrioles otherwise lacking pericentriolar material (PCM), also associated with centriolar fragments in Klp10A mutants, often fraying out from their ends. By the end of G2, Klp10A mutant centrioles displayed discontinuities in the outer microtubules of both basal body-like structures and the short primary cilia that they nucleate. Finally, Klp10A was present along the length of wild-type centrioles, being more concentrated near both ends, but was barely detectable in mutant centrioles (Delgehyr, 2012).

To understand how defective centrioles and centrosomes might arise in Klp10A mutant testes, earlier mitotic stages of spermatogenesis were examined. These showed significantly more cells with either more than (>20% of the cells) or fewer than two Dplp (centriole marker) bodies. Not only the number but also the size of Dplp bodies was compromised: whereas in wild-type spermatogonia, Dplp bodies were of uniform size, Klp10A mutants showed a significant increase in both shorter and longer Dplp bodies. Similar findings were obtained using anti-Spd2 labeling. Examination of spermatogonia by electron microscopy confirmed that Klp10A centrioles were both longer and shorter than wild-type; longer centrioles were generally not uniformly elongated, and shorter ones often appeared tenuously attached to them. This excessive elongation did not, however, seem to prevent formation of procentrioles, indicating that centriole duplication could occur. To better correlate the immunofluorescence observations with electron microscopy, structured illumination microscopy was carried out on anti-Spd2-stained spermatogonial cells. This revealed both shorter and longer centrioles 'frayed' at their ends in Klp10A spermatogonia. Apparent segments of centriolar walls were found both associated with the frayed ends or free in the cytoplasm, suggesting that the elongated structures could become fragmented (Delgehyr, 2012).

To test Klp10A's role in somatic centriole biogenesis, RNA interference (RNAi) was used to efficiently deplete the protein from cultured Dmel cells. Previous studies of the functional requirements for Klp10A for spindle microtubules have not examined centrosome behavior per se. After Klp10A RNAi, cells either lacking or having numerous Dplp bodies were detected. The increase in cells without Dplp bodies was however quite modest, around twice the control. Moreover, the proportion of such cells did not increase following several rounds of Klp10A depletion. This was a quite different outcome from that following depletion of Plk4, a core component of the centrosome duplication pathway, where virtually 100% of cells lose their centrosomes. Accordingly, it was found that centrosomes could reform after Plk4 RNAi treatment in either the presence or absence of Klp10A. Under these conditions, depletion of Sas6, which is known to be essential for centriole duplication, would block de novo centriole formation. Together, these results indicate that the centriole duplication pathway is independent of Klp10A function (Delgehyr, 2012).

It was noticed that Klp10A-depleted cells contained both weakly and brightly fluorescing Dplp bodies. Because it was difficult to measure the length of these bodies (centrioles are less than 0.2 μm in these cells), their fluorescence intensity was measured. Dplp is found at both centrioles and PCM, giving a combined indication of PCM size and centriole length. It was found that Klp10A RNAi resulted in a doubling of both very bright and very weak dots. By contrast, cells depleted for the microtubule depolymerases Klp59C or Klp59D (kinesin-13 family) or Klp67A (kinesin-8) did not show an increase in brightly fluorescent Dplp bodies, suggesting that changes in centrosome size are not a general consequence of cytoplasmic microtubule depolymerization (Delgehyr, 2012).

To understand how these different centrosomal bodies might be generated, video microscopy was carried out to follow centrosomes in cells constitutively expressing GFP-Spd2 from a weak promoter. Because centrosome number is notoriously variable in Dmel cells, cells with two GFP-Spd2 punctae were examined at interphase. In control cells, the two punctae became brighter on mitotic entry as centrosomes recruited PCM and separated to form the spindle poles. Centriole disengagement occurred in telophase, and the daughters had two centrosomal punctae. In Klp10A-depleted cells, the two centrosomes coalesced upon mitotic entry with the apparent collapse of the spindle and bipolarity was recovered; the coalesced centrosomes split into several punctae at one pole, whereas there were none at the other. Centrosomes then dispersed into numerous scattered dots. Thus, in the absence of Klp10A, fragmentation in M phase appears to account for the weak Dplp bodies (Delgehyr, 2012).

It is considered that the weak Dplp bodies could arise by PCM dispersion or centriole fragmentation per se. The former possibility was addressed by staining to reveal Spd2, which makes a greater contribution to PCM, in addition to Dplp. Klp10A depletion led to an increase in small punctae positive for Spd2 but not Dplp, consistent with some PCM fragmentation. In the absence of good antibodies to label centrioles, the possibility of centriole fragmentation was addressed by applying structured illumination immunofluorescence microscopy and electron microscopy to examine centrioles in control and Klp10A-depleted cells. Structured illumination microscopy resolved the punctae staining in control cells into circular structures of ∼0.4 μm outer diameter that, when rotated through 90°, revealed the rod-like structures of centrioles. In Klp10A-depleted cells, these rods could be the same length or longer than in control cells. What appeared to be segments of the centriolar wall was also observed, suggesting that centriole fragmentation could also contribute to the weak Dplp bodies seen by conventional immunofluorescence (Delgehyr, 2012).

Electron microscopy revealed an increase in centrioles longer than 0.18 μm from 15.4% in control cells to 72.1% in Klp10A-depleted cells and a less pronounced increase in centrioles shorter than 0.15 μm (from 12.8% to 17.6%). Moreover, 10.5% of centrioles in Klp10A-depleted cells had an incomplete complement of microtubules. It is possible that the small centrioles represent intermediates in centriole duplication. If so, the relatively small increase in their number suggests that centriole duplication cannot account for the almost doubling of weak Dplp bodies after Klp10A RNAi. Together, these results therefore suggest that Klp10A depletion leads to centriole elongation and fragmentation associated with dispersion of the PCM (Delgehyr, 2012).

Centrosome separation during mitosis is mainly asymmetric in Klp10A-depleted cells: one cell inherits both centrosomes, and the other inherits none. Because the latter cell might be expected to engage in de novo centriole formation, it was wondered whether formation of longer centrioles following Klp10A depletion could be a consequence of this. Therefore centriole reformation was examined after inducing their loss by extensive Plk4 depletion, and it was found that such centrioles were no longer than in control cells. This accords with the normal morphology of centrioles formed de novo in unfertilized eggs overexpressing Plk4. Thus, the long fragmented centrioles seen after Klp10A depletion are unlikely to be a consequence of de novo centriole formation (Delgehyr, 2012).

It was previously found that injection of anti-polyglutamylated tubulin antibody into HeLa cells in G2 resulted in centriole loss and scattering of PCM in a dynein-dependent manner. This has been widely taken to indicate that polyglutamylation might stabilize centrosomes to forces exerted upon them in mitosis. Unlike in mammalian cells, tubulin is not polyglutamylated in most Drosophila tissues, and accordingly this modification could not be detected in Drosophila centrosome preparations or on centrioles of primary spermatocytes or Dmel cells. It was therefore wondered whether centrosomes might scatter following Klp10A downregulation in a dynein-dependent process. To test this, it was decided to partially release tension on centrosomes by depleting dynein (Dhc64, dynein heavy chain 64) in the presence or absence of Klp10A. Because dynein depletion leads to inequitable heritance of centrosomes, their detachment from spindle poles, and cell death, around 50% of the protein was depleted. This did not lead to defects in centrosome number or staining intensity. When Klp10A was extensively depleted and dynein was partially depleted, numbers of weak Dplp bodies decreased at the expense of an increase in bright Dplp bodies as compared to cells depleted for Klp10A alone. Thus, partial depletion of dynein apparently rescues centrosome fragmentation resulting from Klp10A depletion. Electron microscopy revealed that codepletion of Klp10A and dynein resulted in long centrioles, some exceeding the size observed after Klp10A depletion alone. Although the possibility cannot be completely excluded that dynein depletion directly affects the centriole per se, it is more likely that dynein depeletion results in reduced forces upon the centriole, thus protecting the long centrioles of Klp10A-depleted cells from fragmentation (Delgehyr, 2012).

To determine whether Klp10A's microtubule-depolymerizing properties are needed for its centrosomal functions, mutations were generated in two conserved class-specific motifs of its motor domain shown to be essential for microtubule depolymerization in other organisms. These mutations changed residues KVD (aa 317-319) or KEC (aa 546-548) of Klp10A each to three alanines. In accord with the known properties of Klp10A, it was found that high levels of wild-type protein depolymerized interphase microtubules, whereas cells expressing similar levels of the mutant forms had interphase microtubules of normal length. Thus, both mutations abolish Klp10A's microtubule depolymerization activity. Lines expressing either wild-type or mutant forms of GFP-tagged Klp10A were also generated from the endogenous Klp10A promoter that had the 5' but not the 3' untranslated region (UTR) of Klp10A. Both wild-type and mutant forms were expressed at levels comparable to the endogenous protein and were associated with microtubules and centrosomes or spindle poles in interphase and mitosis. Expression of the tagged wild-type protein at these low levels did not result in depolymerization of cytoplasmic microtubules. Then endogenous Klp10A was depleted using RNAi directed at the 3' UTR and the effects upon centrosomes were assessed. This led to an increase in cells either without centrosomes or with both weak and bright Dplp bodies in RNAi-treated cells expressing GFP (control) or GFP-tagged mutant forms of Klp10A, but not in cells expressing GFP-tagged wild-type protein. Thus, generation of both larger centrosomes and centrosome fragments requires loss of the microtubule-depolymerizing activity of Klp10A (Delgehyr, 2012).

Because human CP110 or Centrobin (required for CP110's centriolar localization) results in centriole elongation, it was intriguing to find Drosophila CP110 enriched at the distal ends of the centrioles of primary spermatocytes in a region similar to Klp10A. Moreover, CP110 colocalized with Klp10A in interphase Dmel cells, and other evidence suggested that CP110 and Klp10A can physically interact. It was found that several rounds of CP110 depletion led to an increase in Dmel cells lacking centrosomes, CP110 depletion affects centrosome biogenesis. However, centrosomes could reform after their elimination by Plk4 RNAi treatment, even in the absence of CP110, although this was prevented by further depletion of Sas6, required for bona fide centriolar duplicatio. Thus, there is no absolute requirement for CP110 for centriole duplication. Interestingly, however, there was an increase in weakly fluorescing Dplp bodies in CP110-depleted cells, and electron microscopy revealed that 50% of centrioles were shorter than 0.15 μm, compared to 12.8% in control cells, with most being about 0.11 μm long. This is unlikely to represent an increase in procentrioles, because total centriole number decreased. Centrioles of about 0.11 μm are similar in length to the unit cartwheel made mainly of three or four tiers in Chlamydomonas reinhardtii and may represent the smallest stable centriole structures. Thus, it is concluded that, in contrast to depletion of CP110 in mammalian cells , depletion of CP110 in Drosophila leads to centriole shortening and destabilization (Delgehyr, 2012).

It was then asked whether centriole shortening following CP110 depletion might be rescued by sequentially codepleting Klp10A. It was found that this resulted in the reappearance of long centrioles: 62.5% of the centrioles exceeded 0.18 μm, compared to 15.4% in control cells. When Klp10A was depleted first, followed by codepletion with CP110, the reappearance of longer centrioles was observed. Thus, in the absence of Klp10A, centrioles increase in length regardless of whether CP110 is present or absent. The destabilization of Dplp bodies after CP110 depletion appeared to be enhanced by overexpression of GFP-Klp10A that led to an increased proportion of cells lacking centrosomes after 3 days of CP110 RNAi. Together, these results suggest that CP110 might provide a barrier to prevent Klp10A-mediated depolymerization of centriolar microtubules, and indeed, it forms a plug-like structure at the distal part of the centriole. However, CP110 has no effect on microtubule elongation in the absence of Klp10A. Thus, Klp10A can restrict centriole length regardless of whether or not CP110 is present, and so their physical interaction is not required for Klp10A's recruitment and/or microtubule-depolymerizing activity. Indeed Klp10A may be recruited directly on the centrioles, because it is known to have affinity for the microtubule lattice in vitro (Delgehyr, 2012).

Klp10A is the first kinesin-13 demonstrated to regulate centriole length. Other family members have, however, been shown to regulate the length of flagella and more recently formation of cilia. In contrast to Klp10A, however, the mammalian kinesin-13 Kif24 is further limited to acting from the mother centriole on microtubules of cilia. Thus, Kif24 depletion leads to aberrant cilia formation in cycling cells but does not promote growth of centrioles in nonciliated cells. Although Drosophila Klp10A and mammalian Kif24 act differently, both are able to interact with CP110. However, the interaction of CP110 and Kif24 in mammalian cells affects only the process of cilium formation. These functional differences between kinesin-13:CP110 complexes could reflect a regulative adaptation by mammals associated with evolution of the ability to generate primary cilia in many cell types. Thus, whereas in Drosophila, where few cells are ciliated, the capping function of CP110 might help to fix the length of the centriole by blocking Klp10A-mediated microtubule depolymerization, in mammals it has the additional function of blocking cilium formation until the correct phase of the cell cycle. Whether in mammals another kinesin-13 might play the role of Klp10A in regulating centriole length remains an open question (Delgehyr, 2012).

Stepwise evolution of the centriole-assembly pathway

CP110 only appears in animals, and is absent from yeast and plants. It localizes to a distal centriole compartment, and is needed for centriole reduplication in S-phase-arrested human cells and to define centriole length. It is hypothesized that CP110 was added to the centriole-assembly pathway in animals as an innovation. A binding partner of CP110, CEP97, has a very similar phylogenetic distribution to CP110. These results both suggest that the two proteins might work in a complex in all animals and validate the use of phylogenetic distributions as a screening strategy to find potential binding partners. Drosophila CP110 and CEP97 localize to centrioles and are necessary for centriole duplication in S2 cells. CP110 in humans participates in other processes, such as preventing centrioles from nucleating cilia and cytokinesis. It has been proposed that centrioles might play an important role in signaling the event of cellular abscission in cytokinesis. It is possible that CP110 emerged in animals to allow further coordination of centriole duplication with ciliogenesis and/or cytokinesis (Carvalho-Santos, 2010).


Search PubMed for articles about Drosophila CP110

Carvalho-Santos, Z., Machado, P., Branco, P., Tavares-Cadete, F., Rodrigues-Martins, A., Pereira-Leal, J. B. and Bettencourt-Dias, M. (2010). Stepwise evolution of the centriole-assembly pathway. J Cell Sci 123: 1414-1426. PubMed ID: 20392737

Chen, Z., Indjeian, V. B., McManus, M., Wang, L. and Dynlacht, B. D. (2002). CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells. Dev Cell 3: 339-350. PubMed ID: 12361598

D'Angiolella, V., Donato, V., Vijayakumar, S., Saraf, A., Florens, L., Washburn, M. P., Dynlacht, B. and Pagano, M. (2010). SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation. Nature 466: 138-142. PubMed ID: 20596027

Delgehyr, N., (2012). Klp10A, a microtubule-depolymerizing kinesin-13, cooperates with CP110 to control Drosophila centriole length. Curr Biol. 22(6): 502-9. PubMed ID: 22365849

Franz, A., Roque, H., Saurya, S., Dobbelaere, J. and Raff, J. W. (2013). CP110 exhibits novel regulatory activities during centriole assembly in Drosophila. J Cell Biol 203: 785-799. PubMed ID: 24297749

Kobayashi, T., Tsang, W. Y., Li, J., Lane, W. and Dynlacht, B. D. (2011). Centriolar kinesin Kif24 interacts with CP110 to remodel microtubules and regulate ciliogenesis. Cell 145: 914-925. PubMed ID: 21620453

Li, J., D'Angiolella, V., Seeley, E. S., Kim, S., Kobayashi, T., Fu, W., Campos, E. I., Pagano, M. and Dynlacht, B. D. (2013). USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110. Nature 495: 255-259. PubMed ID: 23486064

Spektor, A., Tsang, W. Y., Khoo, D. and Dynlacht, B. D. (2007). Cep97 and CP110 suppress a cilia assembly program. Cell 130: 678-690. PubMed ID: 17719545

Tsang, W. Y., Bossard, C., Khanna, H., Peranen, J., Swaroop, A., Malhotra, V. and Dynlacht, B. D. (2008). CP110 suppresses primary cilia formation through its interaction with CEP290, a protein deficient in human ciliary disease. Dev Cell 15: 187-197. PubMed ID: 18694559

Biological Overview

date revised: 5 March 2014

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