Regulation of centriolar satellite integrity and its physiology
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Centriolar satellites comprise cytoplasmic granules that are located around the centrosome. Their molecular identification was first reported more than a quarter of a century ago. These particles are not static in the cell but instead constantly move around the centrosome. Over the last decade, significant advances in their molecular compositions and biological functions have been achieved due to comprehensive proteomics and genomics, super-resolution microscopy analyses and elegant genetic manipulations. Centriolar satellites play pivotal roles in centrosome assembly and primary cilium formation through the delivery of centriolar/centrosomal components from the cytoplasm to the centrosome. Their importance is further underscored by the fact that mutations in genes encoding satellite components and regulators lead to various human disorders such as ciliopathies. Moreover, the most recent findings highlight dynamic structural remodelling in response to internal and external cues and unexpected positive feedback control that is exerted from the centrosome for centriolar satellite integrity.
KeywordsCellular stress Centriole Ciliogenesis MSD1/SSX2IP Microtubule PCM1 PLK4 Phosphorylation Ubiquitylation
Spindle pole body
The centrosome plays multiple roles in many biological processes including cell proliferation, differentiation and development [1, 2, 3, 4]. Since this structure was originally discovered by Edouard Van Beneden in 1883, and later named and further described by Theodor Boveri in 1888 [5, 6, 7], it has generally been accepted that most, if not all, of its cellular functions are executed through microtubule-organising activities; the centrosome is deemed to be a major microtubule-organising centre (MTOC) in animal somatic cells. Microtubules, dynamic hollow biopolymers composed of α-/β-tubulin heterodimers, are nucleated from the centrosome and thereby play diverse cellular roles in various processes including cell cycle progression, chromosome segregation, cell motility and polarisation, cell fate determination and ciliogenesis [8, 9, 10, 11, 12, 13, 14].
PCM1 was initially identified in human cells using human autoimmune antiserum , followed by cloning of its homologous gene from frog . It is generally accepted that PCM1 comprises a structural platform for centriolar satellites; when PCM1 becomes dysfunctional, either by depletion, deletion or mutation, satellite particles disassemble. Therefore, the evaluation of new proteins as components of centriolar satellites is formally made according to the following two criteria: the first is colocalisation and physical interaction with PCM1, and the second is delocalisation from pericentrosomal locations upon PCM1 depletion [19, 20, 21, 22, 23, 24].
A complete picture with regards to the full set of satellite components and the spatiotemporal constitution of centriolar satellites has not yet been established because the number of proteins identified as satellite components has continued to increase over the last several years. There were reported to be 11 in 2011 , ~30 in 2014  and >100 according to the most recent studies [26, 27, 28, 29, 30, 31, 32] (Fig. 1c). The two main cellular functions of centriolar satellites, ciliogenesis and microtubule organisation, had already been posited by two earlier pioneering studies [17, 33]. Furthermore, genes encoding centriolar satellite components or regulatory proteins involved in centriolar satellite integrity have been identified as some that cause ciliopathy-related human diseases when mutated; these include Bardet–Biedl syndrome, Joubert syndrome, Meckel Gruber syndrome, primary microcephaly (MCPH) and oral-facial-digital syndrome [31, 34, 35, 36, 37, 38, 39, 40, 41]. Molecular understanding of the cellular functions of centriolar satellites has increased, and further, broader roles than previously thought, such as those in autophagy and actin filament nucleation/organisation, have started to emerge [42, 43, 44, 45]. We have been witnessing an exiting era in which not only the comprehensive structural constituents but also the physiologies of centriolar satellites have been uncovered. This review focuses on describing recent advances in the cellular regulation of centriolar satellite integrity and its physiological significances (please refer to excellent earlier reviews on centriolar satellite structures and functions) [16, 25].
Intrinsic control of centriolar satellite integrity
PCM1 as a structural platform
Interaction of PCM1 with other satellite components
In addition to BBS4 and OFD1, depletion of several other satellite components impairs the pericentriolar patterns of centriolar satellite localisation to varying degrees. These include CCDC11 , CCDC12 , CCDC13 , CCDC14 [23, 26], CCDC18 , CCDC66 , CEP63 [23, 51, 52, 53], CEP72 , CEP90 [55, 56], CEP126 , CEP131/AZI1 [26, 58, 59, 60], CEP290 (also called NPHP6) [38, 61, 62, 63], FOR20 , HAP1 and HTT [36, 65], KIAA0753 , Par6α  and SDCCAG8 . However, in most of these cases, the underlying molecular mechanisms by which centriolar satellite integrity is disturbed have not yet been explored, and it remains to be determined whether alterations of centriolar satellite distributions are due to the failure of PCM1 oligomerisation, the compromised interaction of PCM1 with other components or perturbation of the association of PCM1 particles with microtubules (see below). It would be important to clarify whether these alterations of satellite patterns correspond to the disappearance, reduced numbers, lower intensities or spatial dispersion of centriolar satellite particles (Fig. 2b). Thus, how centriolar satellite integrity is intrinsically established is one of the critical issues to be addressed in the future.
The microtubule cytoskeleton
Association and transport
Centriolar satellites are localised along microtubules emanating from the centrosome. An intact microtubule network is essential to maintain centriolar satellite integrity because depolymerisation of microtubules by anti-microtubule agents such as Nocodazole or cold treatment results in the dispersion of satellite particles from the pericentriolar region towards the entire cytoplasm (Fig. 2a, b) [17, 33, 46]; consistent with this, knocking down a series of microtubule machinery (ANK2, DCTN1, MAPT, MAP7D1, MAP9, MAP7D3 and MAPRE3) affects intensities of centriolar satellites . Satellite particles associated with microtubules are not static within a cell. Instead, particles rapidly and continuously move around the centrosome. The majority of particles appear to move towards the centrosome, and consequently these particles were originally termed satellites . However, the precise manner of centriolar satellites movements in the proximity of centrosomes and the regulation of their steady state at this position are still unknown. Therefore, the dynamics of centriolar satellites in various conditions is a major question to be addressed in the field.
Despite this situation, it is shown that centrosome-oriented directional movement of centriolar satellites, at least in part, is driven by cytoplasmic dynein. The dynein complex physically interacts with satellite components , and the perturbation of dynein functions [68, 69] results in the dispersion of centriolar satellites [19, 33]. Depletion of two satellite components, CEP72 and CEP290, also results in the aggregation of centriolar satellites, which is attributed to the defective dissociation of centriolar satellites from dynein [20, 70] (Fig. 2b). Nonetheless, how PCM1 and hence centriolar satellites interact with the dynein complex remains to be established, although BBS4  and Par6α  are reported to be required for the association between PCM1 and the dynein complex.
Delivery of microtubule-anchoring and other regulatory factors to the centrosome
A large number of centriole/centrosome proteins are transported along with centriolar satellites as cargo molecules in a dynein-dependent manner . The recently identified microtubule-anchoring factor MSD1/SSX2IP is one of these (see “Box for a detailed description of MSD1/SSX2IP”). In support of the significance of MSD1/SSX2IP localisation to centriolar satellites, depletion of PCM1, which disperses MSD1/SSX2IP from satellites, also results in microtubule-anchoring defects [24, 33]. Similar microtubule defects are also reported upon depletion of a series of satellite components that are required for proper localisation of PCM1 to the pericentriolar region; these include CEP90 [55, 56], FOR20 , HOOK3  and Par6α . Other proteins including CAP350, FOP, Ninein, ODF2/Cenexin1 and Trichoplein, among which FOP is a centriolar satellite component, are also involved in microtubule anchoring [33, 71, 72, 73, 74, 75]. However, it remains to be determined how these factors tether microtubules and whether these proteins physically/functionally interact with MSD1/SSX2IP. It is noteworthy that MSD1/SSX2IP may play a role in PCM1 localisation and centriolar satellite integrity independent of the microtubule anchoring; MSD1/SSX2IP could directly be involved in centriole satellite integrity.
Interestingly, in contrast to PCM1 depletion, which leads to the dispersion/disappearance of centriolar satellites [19, 33], knockdown of MSD1/SSX2IP renders the microtubule network present yet completely disorganised and importantly gives rise to the abnormal aggregation of larger satellite particles in the vicinity of the centrosome (Fig. 2b). Furthermore, these satellite particles are stuck at the minus ends of disorganised microtubules with greatly reduced motility [24, 26, 28].
Centriole assembly and centrosome copy number
Intriguingly, upon MSD1/SSX2IP depletion in U2OS and many other cancer cells, satellite aggregates contain, besides constitutive satellite components, a number of structural constituents of centrioles/centrosomes that are not normally localised to centriolar satellites. These include centrin (normally localises to the distal lumen of centrioles) [76, 77], centrobin (the daughter centriole) , CEP164 (the distal appendages) , C-NAP1 (the proximal end)  and CP110 (the distal end) . It is of note that centriolar satellites are not responsible for transport of all the centrosome/centriole components. For instance, PLK4 (the proximal end) , CEP152 (the proximal end) [83, 84], hSAS-6 (procentriole) , pericentrin (PCM)  and γ-tubulin (the PCM)  do not accumulate as satellite aggregates upon depletion of MSD1/SSX2IP .
Electron and super-resolution fluorescence microscopy analyses revealed that depletion of MSD1/SSX2IP leads to compromised centriole morphologies. Under this condition, cylindrical centriole structures tend to be lost and centriolar proteins that accumulate within satellite aggregates are not localised to the normal centriolar position . These results are perfectly in line with earlier studies that showed centriolar satellites are important for proper centrosome/basal body assembly [19, 20, 33, 88]. Consistent with compromised centriole assembly, MSD1/SSX2IP-depleted cells are insensitive to PLK4 overproduction, which otherwise induces centriole/centrosome overamplification using a pre-existing centriole as a template [82, 89, 90, 91].
Remarkably, U2OS cells in which MSD1/SSX2IP is depleted exhibit accelerated centrosome reduplication upon hydroxyurea (HU)-mediated arrest [92, 93], which might look like the opposing impact exerted by MSD1/SSX2IP depletion under PLK4 overproduction described earlier. One possible scenario is that because several centriolar components prematurely accumulate in satellites upon MSD1/SSX2IP depletion, these cells are likely to undergo faster and more efficient overamplification of centrosomes. Similar, if not identical, accumulation of satellite aggregates (supernumerary centriole-related structures) is reported upon depletion of CEP131/AZI1  and CCDC14 , suggesting that these two proteins are involved in transport of centrosomal/centriolar proteins from the cytoplasm to the centrosome/centriole and may functionally interact with MSD1/SSX2IP.
Centriolar satellites ensure centriole duplication by helping assembly of a series of centriolar/centrosomal components including CEP63, CDK5RAP2/CEP219 [94, 95], CEP152 and WDR62 [96, 97], thereby securing centrosome recruitment of CDK2 , a critical regulator of centrosome duplication [98, 99]. Intriguingly, these assembled centriolar/centrosomal components are collectively termed MCPH-associated proteins because mutations in the corresponding genes are identified in human patients suffering from MCPH [100, 101]. These results highlight the complex, multi-layered roles of centriolar satellites; centriolar satellite integrity plays both positive and negative roles in centriole/centrosome assembly and duplication. A similar dual role of centriolar satellites in ciliogenesis was also reported . This raises the intriguing possibility that each particle of centriolar satellites may not be equal in its composition, but instead they may be composed of various combinations of satellite components and regulators, which serve a diverse set of functions.
Cell cycle-dependent regulation of centriolar satellite organisation
The cellular localisation of centriolar satellites exhibits dynamic behaviour during the cell cycle. In the very first study of human PCM1 , the authors found that the centrosomal signals detected with anti-PCM1 antibodies were reduced during G2 phase, remained low in M phase and then increased towards the following G1 phase, although the antibodies used seemed to fail to recognise the pericentrosomal localisation of PCM1. The notion that centriolar satellites completely disassemble and disappear from pericentrosomal regions during M phase varies among subsequently published studies; some detected mitotic satellite signals of PCM1 , while others claimed that these signals exhibited reduced intensities or even disappeared [16, 19, 24, 46]. It would be fair to describe that their mitotic intensities at the pericentrosomal region are more or less decreased during mitosis (Fig. 2a), although this does not imply that centriolar satellites do not play any physiological roles in M phase. In fact, PCM1 reportedly is involved in spindle pole integrity during metaphase . How this spatial regulation of centriolar satellites materialises at the molecular level remains elusive, and this area has been poorly characterised.
Another interesting issue with regards to cell cycle-dependent regulation of centriolar satellite integrity arises when cells exit from mitosis and initiate ciliogenesis. Under this condition, depletion of TALPID3 and/or CEP290 leads to an aberrant distribution of centriolar satellites . TALPID3 is known to be localised to the extreme distal end of centrioles and required at least during ciliogenesis for proper localisation of Rab8a, a key small GTPase involved in protein trafficking. It would be of great interest to explore how TALPID3, CEP290 and Rab8a regulate centriolar satellite integrity outside the mitotic cycle.
Cellular stress responses and centriolar satellite integrity
Remodelling of centriolar satellites upon cellular stress through the p38-SAPK signalling pathway
In addition to satellite remodelling, cellular stresses inhibit MIB1, an E3 ubiquitin ligase enzyme that is also a component of centriolar satellites. Interestingly, MIB1 inhibition is independent of p38 activation . Thus, it appears that exposure to cellular stresses impacts on two bifurcated downstream branches; one is p38-mediated centriolar satellite remodelling, while the other is p38-independent inhibition of MIB1 that ubiquitylates PCM1, CEP131/AZI1 and CEP290. Neither MIB1 nor MIB1-mediated ubiquitylation of PCM1 and CEP131/AZI1 plays any roles in the association of CEP131/AZI1 and PCM1 with centriolar satellites, indicating that MIB1 is not involved in overall centriolar satellite integrity . Under non-stressed conditions, MIB1 actively ubiquitylates PCM1, CEP131/AZ1 and CEP290, which suppresses the interaction between CEP131/AZI1 and PCM1 and simultaneously inhibits ciliogenesis. Upon exposure to stresses, satellite remodelling occurs, leading to promotion of cilia formation .
More recent work shows that PCM1 in turn is essential for tethering MIB1 to centriolar satellites. In PCM1 knockout human cells, MIB1 becomes localised to the centrosome, thereby destabilising TALPID3 through poly-ubiquitylation. The consequent reduction of TALPID3 leads to abrogation of recruitment of ciliary vesicles, resulting in suppression of cilium assembly . It would be worth pointing out that whether the MIB1 ubiquitin ligase catalyses mono-ubiquitylation  or poly-ubiquitylation (and destabilisation) of PCM1 and CEP131/AZI1  remains to be solved. In addition to centriolar satellite components (CEP131/AZI1, CEP290 and PCM1), MIB1 ubiquitylates PLK4, which leads to degradation of this protein . This role of MIB1 in PLK4 stability may at least in part account for the negative role of this ubiquitin ligase in ciliogenesis as well as MIB1-mediated destabilisation of TALPID3 [32, 112]. Admittedly a complicated network is in action to regulate centriolar satellite integrity through the MIB1-ubiquitin pathway and its substrates.
It is of interest to point out that satellite-localising PCM1 is generally believed to be important to promote ciliogenesis [19, 20, 109, 113]. The result described earlier clearly indicates a more complex mode of centriolar satellite functions in controlling ciliogenesis because dispersed PCM1 (forming a complex with CEP131/AZI1) is still able to promote or even more potently induce ciliogenesis . It should also be noted that, under stress conditions, centriolar satellites (detected by OFD1) are devoid of PCM1, CEP131/AZI1 and CEP290, which become dispersed. This implies that, as mentioned earlier, centriolar satellites comprise multiple particles with distinct constituents and that even PCM1-independent centriolar satellites may exist upon exposure to certain cellular stresses . Unlike the prevailing view that PCM1 is the main structural platform for centriolar satellites, the composition and organisation of centriolar satellites would be rewired within various environmental, developmental and cell cycle contexts. More work including electron microscopy and proteomics is necessary to further explore these intriguing findings.
DNA damage-induced centrosome overamplification and the DNA damage checkpoint
DNA damage imposed by ionising radiation (IR) or chemicals such as Bleomycin induces centrosome amplification via formation of excessive centriolar satellites (Figs. 2a, b, 4) . The DNA damage checkpoint signalling pathway mediated by CHK1 is activated under this condition and is essential for this response. An earlier report regarding the role of centriolar satellites as intermediate precursors for centrosome amplification is consistent with this finding . Prolonged G2 arrest leads to centrosome overamplification . Therefore, it is likely that IR or Bleomycin activates the DNA damage checkpoint, which leads to G2 delay, thereby inducing centrosome overamplification.
It is worth noting that DNA damage appears to give rise to two different, apparently opposing effects on centriolar satellite integrity. On one hand, it results in the remodelling of centriolar satellites, in which PCM1 as well as CEP131/AZI1 and CEP290 becomes dispersed away from the pericentriolar region, and yet promotes ciliogenesis [58, 111]. On the other hand, it leads to centrosome overproduction using centriolar satellites as intermediate precursors (Fig. 4) . To reconcile these results, we point out a few differences in experimental procedures between the two situations. One lies in the DNA-damaging methods and downstream pathways that are activated. The former studies [58, 111] used UV treatment, which activates the p38-SAPK pathway, while the latter study  used IR and Bleomycin, which activate the CHK1-DNA damage checkpoint pathway. The second difference is the experimental timeline. In the former reports [58, 111], acute responses were observed (1 h after UV treatment), while in the latter report , cells were observed at much later time points (24–72 h after irradiation). In any case, collectively, these findings uncovered the hitherto unknown spatiotemporal dynamics of centriolar satellite organisation upon exposure to various types of cellular stresses.
An unexpected role of PLK4 in centriolar satellite integrity and ciliogenesis
Phosphorylation of PCM1 by PLK4
As described earlier, centriolar satellites play a critical role in centriole/centrosome assembly and ciliogenesis. Is there any converse regulation? A recent study showed that this is indeed the case . PLK4 is regarded as a rate-limiting master regulator of centriole copy number control because centrioles fail to duplicate when PLK4 malfunctions but conversely undergo overamplification when PLK4 is overproduced [82, 118, 119, 120]. PLK4 plays an essential role during mouse development [121, 122]. Furthermore, the importance of PLK4 for proper cell proliferation and differentiation in humans is underpinned by recent studies demonstrating that mutations in PLK4 lead to primordial dwarfism and that abnormal gene amplification results in human embryos exhibiting aneuploidy [123, 124, 125]. Several in vivo substrates in addition to PLK4 itself  have been identified that are localised to the centriole/centrosome and play an important role in centriole duplication. These include STIL/hSAS-5 [127, 128, 129], FBXW5 (a component of the SCFFBXW5 ubiquitin ligase)  and GCP6 (a component of the γ-tubulin complex, γ-TuC) [131, 132]. These results led to the consensus in the field that PLK4 exerts its critical role in centriole duplication through phosphorylating centriole/centrosome components [123, 133].
Introduction of the non-phosphorylatable PCM1 mutant (PCM1-S372A) recapitulates the phenotypes of PLK4-depleted and kinase-dead PLK4-expressing cells. Conversely, the phosphomimetic mutant (PCM1-S372D/E) rescues the dispersed centriolar satellite patterns (Figs. 2b, 5b); however, the suppression is only partial and under this condition centriolar satellites are localised only around the centrosome in a more concentrated, non-motile manner. Importantly, PCM1 phosphorylation is required to promote ciliogenesis, which is independent of centriole duplication .
What are the molecular consequences of PCM1 phosphorylation in terms of the maintenance of centriolar satellite integrity? Two functions of PCM1 crucial for ensuring centriolar satellite organisation are regulated by PLK4-mediated phosphorylation. The first is PCM1 self-dimerisation and the second is the interaction of PCM1 with BBS4 and CEP290, two components of centriolar satellites. In line with these results, S372 is located in the region of the second coiled domain of PCM1, which is important for protein–protein interactions . Cumulatively, these findings revise our current view with regards to PLK4 functions and centriole satellite integrity; PLK4 plays a decisive role in centriole duplication by phosphorylating not only centriole/centrosome components, but also PCM1, which in turn secures centriole/centrosome assembly.
As described earlier, centriolar satellites disassemble during mitosis and reassemble in the following G1 phase [19, 33]. Given that PCM1 is phosphorylated not only by PLK4 but also by CDK1 and PLK1 [136, 137], it is tempting to speculate that CDK1- and/or PLK1-dependent phosphorylation promotes satellite disassembly during M phase, followed by PLK4-mediated phosphorylation of S372 during G1 phase, which promotes reassembly of centriolar satellites. This dual phospho-regulation or PCM1 may underlie at least in part the temporal regulation of cell cycle-dependent satellite organisation and remodelling. It is worth noting that it was recently shown that CDK1 and PLK4 play antagonistic roles in centriole duplication, negative and positive, respectively, through phosphorylation of STIL in a cell cycle-dependent manner .
It is generally believed that ciliogenesis defects observed in cells in which PLK4 is depleted by siRNA, inactivated by a small molecule inhibitor or mutated are attributed to centriole duplication defects [123, 133]. However, under these conditions, centrioles and basal bodies still exist [123, 138]. It is, therefore, possible that the complete disappearance of the centriole/basal body is not an absolute prerequisite for ciliogenesis defects derived from PLK4 dysfunction. A higher level of PLK4 activity may be required for centriolar satellite integrity than for centriole duplication. PLK4 likely potentiates ciliogenesis to some degree through PCM1 phosphorylation. This safeguards centriolar satellite integrity, promotes delivery of ciliary components to the basal body and helps to build these structures. Therefore, PLK4 inactivation may induce anomalies in humans to some extent through centriolar satellite dispersion leading to ciliogenesis failure; this may account for the underlying aetiology of defective cilia diagnosed in human diseases caused by PLK4 mutations.
Autophagy and centriolar satellite integrity
An unexpected functional link was recently uncovered between autophagy and centriolar satellite integrity [42, 43, 139]. In proliferating cells in nutrient-rich conditions, basal autophagy inhibits ciliogenesis by degrading IFT20, an essential protein for primary cilium formation . Under this condition, OFD1 locating at centriolar satellites is a critical player in this inhibition . By contrast, upon serum deprivation, which induces both ciliogenesis and autophagy, induced autophagy actively degrades OFD1, thereby promoting ciliogenesis.
A positive role of PCM1, a platform for centriolar satellites, in ciliogenesis is well established [19, 20, 109, 112]. This positive function is executed through satellite- and microtubule-mediated transport of proteins required for basal body assembly and primary cilium biogenesis . Thus, centriolar satellites play both positive and negative roles in ciliogenesis. As mentioned earlier, various cellular stresses promote ciliogenesis through satellite remodelling, in which OFD1 forms non-canonical centriolar satellites without PCM1 [58, 111]. Given the inhibitory role of OFD1 in ciliogenesis, OFD1-containing satellites assembled under acute stress conditions may represent the inactive form of OFD1 (e.g. the sequestration of OFD1 as abortive aggregates), thereby eliminating its inhibitory impact on ciliogenesis. It would be of great interest to dissect the comprehensive molecular composition of centriolar satellites under serum starvation conditions, to decipher to what extent centriole satellites are remodelled and to finally explore the mechanism by which satellite remodelling is induced.
Neurogenesis and PCM1
One recent report  shows that a microRNA, called miR-128, negatively regulates the cellular levels of PCM1. Overexpression of miR-128 resulted in downregulation of PCM1, leading to repressing proliferation of neural progenitor cells yet simultaneously promoting their differentiation into neurons. Conversely, the reduction of miR-128 elicited the opposite effects; promotion of proliferation and suppression of differentiation of neural progenitor cells . Whether this inhibitory role of PCM1 in neurogenesis is exerted through centriolar satellite integrity is yet to be rigorously examined, but this would be a novel, intriguing aspect of the physiology of centriolar satellites.
We thank Noriaki Sasai for critical reading of the manuscript and helpful comments. This work was supported by Cancer Research UK/The Francis Crick Institute, Hiroshima University, the Japan Society for the Promotion of Science KAKENHI Scientific Research (A) (16H02503) and Challenging Exploratory Research (16K14672) (T.T.) and the Nara Institute of Science and Technology (A.H.).
- 22.Barenz F, Inoue D, Yokoyama H, Tegha-Dunghu J, Freiss S, Draeger S, Mayilo D, Cado I, Merker S, Klinger M, Hoeckendorf B, Pilz S, Hupfeld K, Steinbeisser H, Lorenz H, Ruppert T, Wittbrodt J, Gruss OJ (2013) The centriolar satellite protein SSX2IP promotes centrosome maturation. J Cell Biol 202:81–95PubMedPubMedCentralCrossRefGoogle Scholar
- 26.Gupta GD, Coyaud E, Goncalves J, Mojarad BA, Liu Y, Wu Q, Gheiratmand L, Comartin D, Tkach JM, Cheung SW, Bashkurov M, Hasegan M, Knight JD, Lin ZY, Schueler M, Hildebrandt F, Moffat J, Gingras AC, Raught B, Pelletier L (2015) A dynamic protein interaction landscape of the human centrosome-cilium interface. Cell 163:1484–1499PubMedPubMedCentralCrossRefGoogle Scholar
- 31.Kodani A, Yu TW, Johnson JR, Jayaraman D, Johnson TL, Al-Gazali L, Sztriha L, Partlow JN, Kim H, Krup AL, Dammermann A, Krogan NJ, Walsh CA, Reiter JF (2015) Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication. eLife 4:e07519PubMedCentralCrossRefGoogle Scholar
- 34.Stephen LA, Tawamie H, Davis GM, Tebbe L, Nurnberg P, Nurnberg G, Thiele H, Thoenes M, Boltshauser E, Uebe S, Rompel O, Reis A, Ekici AB, McTeir L, Fraser AM, Hall EA, Mill P, Daudet N, Cross C, Wolfrum U, Jamra RA, Davey MG, Bolz HJ (2015) TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23). eLife 4:e08077PubMedPubMedCentralCrossRefGoogle Scholar
- 35.Romio L, Wright V, Price K, Winyard PJ, Donnai D, Porteous ME, Franco B, Giorgio G, Malcolm S, Woolf AS, Feather SA (2003) OFD1, the gene mutated in oral-facial-digital syndrome type 1, is expressed in the metanephros and in human embryonic renal mesenchymal cells. J Am Soc Nephrol 14:680–689PubMedCrossRefGoogle Scholar
- 37.Chevrier V, Bruel AL, Van Dam TJ, Franco B, Lo Scalzo M, Lembo F, Audebert S, Baudelet E, Isnardon D, Bole A, Borg JP, Kuentz P, Thevenon J, Burglen L, Faivre L, Riviere JB, Huynen MA, Birnbaum D, Rosnet O, Thauvin-Robinet C (2016) OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digital syndrome. Hum Mol Genet 25:497–513PubMedCrossRefGoogle Scholar
- 38.Valente EM, Silhavy JL, Brancati F, Barrano G, Krishnaswami SR, Castori M, Lancaster MA, Boltshauser E, Boccone L, Al-Gazali L, Fazzi E, Signorini S, Louie CM, Bellacchio E, Bertini E, Dallapiccola B, Gleeson JG (2006) Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nat Genet 38:623–625PubMedCrossRefGoogle Scholar
- 40.Coene KL, Roepman R, Doherty D, Afroze B, Kroes HY, Letteboer SJ, Ngu LH, Budny B, van Wijk E, Gorden NT, Azhimi M, Thauvin-Robinet C, Veltman JA, Boink M, Kleefstra T, Cremers FP, van Bokhoven H, de Brouwer AP (2009) OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin. Am J Hum Genet 85:465–481PubMedPubMedCentralCrossRefGoogle Scholar
- 41.Sang L, Miller JJ, Corbit KC, Giles RH, Brauer MJ, Otto EA, Baye LM, Wen X, Scales SJ, Kwong M, Huntzicker EG, Sfakianos MK, Sandoval W, Bazan JF, Kulkarni P, Garcia-Gonzalo FR, Seol AD, O’Toole JF, Held S, Reutter HM, Lane WS, Rafiq MA, Noor A, Ansar M, Devi AR, Sheffield VC, Slusarski DC, Vincent JB, Doherty DA, Hildebrandt F, Reiter JF, Jackson PK (2011) Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 145:513–528PubMedPubMedCentralCrossRefGoogle Scholar
- 47.Kim JC, Badano JL, Sibold S, Esmail MA, Hill J, Hoskins BE, Leitch CC, Venner K, Ansley SJ, Ross AJ, Leroux MR, Katsanis N, Beales PL (2004) The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat Genet 36:462–470PubMedCrossRefGoogle Scholar
- 58.Villumsen BH, Danielsen JR, Povlsen L, Sylvestersen KB, Merdes A, Beli P, Yang YG, Choudhary C, Nielsen ML, Mailand N, Bekker-Jensen S (2013) A new cellular stress response that triggers centriolar satellite reorganization and ciliogenesis. EMBO J 32:3029–3040PubMedPubMedCentralCrossRefGoogle Scholar
- 61.Chang B, Khanna H, Hawes N, Jimeno D, He S, Lillo C, Parapuram SK, Cheng H, Scott A, Hurd RE, Sayer JA, Otto EA, Attanasio M, O’Toole JF, Jin G, Shou C, Hildebrandt F, Williams DS, Heckenlively JR, Swaroop A (2006) In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum Mol Genet 15:1847–1857PubMedPubMedCentralCrossRefGoogle Scholar
- 63.Sayer JA, Otto EA, O’Toole JF, Nurnberg G, Kennedy MA, Becker C, Hennies HC, Helou J, Attanasio M, Fausett BV, Utsch B, Khanna H, Liu Y, Drummond I, Kawakami I, Kusakabe T, Tsuda M, Ma L, Lee H, Larson RG, Allen SJ, Wilkinson CJ, Nigg EA, Shou C, Lillo C, Williams DS, Hoppe B, Kemper MJ, Neuhaus T, Parisi MA, Glass IA, Petry M, Kispert A, Gloy J, Ganner A, Walz G, Zhu X, Goldman D, Nurnberg P, Swaroop A, Leroux MR, Hildebrandt F (2006) The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 38:674–681PubMedCrossRefGoogle Scholar
- 95.Bond J, Roberts E, Springell K, Lizarraga SB, Scott S, Higgins J, Hampshire DJ, Morrison EE, Leal GF, Silva EO, Costa SM, Baralle D, Raponi M, Karbani G, Rashid Y, Jafri H, Bennett C, Corry P, Walsh CA, Woods CG (2005) A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat Genet 37:353–355PubMedCrossRefGoogle Scholar
- 96.Yu TW, Mochida GH, Tischfield DJ, Sgaier SK, Flores-Sarnat L, Sergi CM, Topcu M, McDonald MT, Barry BJ, Felie JM, Sunu C, Dobyns WB, Folkerth RD, Barkovich AJ, Walsh CA (2010) Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet 42:1015–1020PubMedPubMedCentralCrossRefGoogle Scholar
- 97.Nicholas AK, Khurshid M, Desir J, Carvalho OP, Cox JJ, Thornton G, Kausar R, Ansar M, Ahmad W, Verloes A, Passemard S, Misson JP, Lindsay S, Gergely F, Dobyns WB, Roberts E, Abramowicz M, Woods CG (2010) WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat Genet 42:1010–1014PubMedCrossRefGoogle Scholar
- 104.Fogeron ML, Muller H, Schade S, Dreher F, Lehmann V, Kuhnel A, Scholz AK, Kashofer K, Zerck A, Fauler B, Lurz R, Herwig R, Zatloukal K, Lehrach H, Gobom J, Nordhoff E, Lange BM (2013) LGALS3BP regulates centriole biogenesis and centrosome hypertrophy in cancer cells. Nat Commun 4:1531PubMedCrossRefGoogle Scholar
- 106.Chen CT, Hehnly H, Yu Q, Farkas D, Zheng G, Redick SD, Hung HF, Samtani R, Jurczyk A, Akbarian S, Wise C, Jackson A, Bober M, Guo Y, Lo C, Doxsey S (2014) A unique set of centrosome proteins requires pericentrin for spindle-pole localization and spindle orientation. Curr Biol 24:2327–2334PubMedPubMedCentralCrossRefGoogle Scholar
- 111.Tollenaere MA, Villumsen BH, Blasius M, Nielsen JC, Wagner SA, Bartek J, Beli P, Mailand N, Bekker-Jensen S (2015) p38- and MK2-dependent signalling promotes stress-induced centriolar satellite remodelling via 14-3-3-dependent sequestration of CEP131/AZI1. Nat Commun 6:10075PubMedPubMedCentralCrossRefGoogle Scholar
- 123.Martin CA, Ahmad I, Klingseisen A, Hussain MS, Bicknell LS, Leitch A, Nurnberg G, Toliat MR, Murray JE, Hunt D, Khan F, Ali Z, Tinschert S, Ding J, Keith C, Harley ME, Heyn P, Muller R, Hoffmann I, Daire VC, Dollfus H, Dupuis L, Bashamboo A, McElreavey K, Kariminejad A, Mendoza-Londono R, Moore AT, Saggar A, Schlechter C, Weleber R, Thiele H, Altmuller J, Hohne W, Hurles ME, Noegel AA, Baig SM, Nurnberg P, Jackson AP (2014) Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat Genet 46:1283–1292PubMedPubMedCentralCrossRefGoogle Scholar
- 129.Zitouni S, Francia ME, Leal F, Montenegro Gouveia S, Nabais C, Duarte P, Gilberto S, Brito D, Moyer T, Kandels-Lewis S, Ohta M, Kitagawa D, Holland AJ, Karsenti E, Lorca T, Lince-Faria M, Bettencourt-Dias M (2016) CDK1 prevents unscheduled PLK4-STIL complex assembly in centriole biogenesis. Curr Biol 26:1127–1137PubMedCrossRefGoogle Scholar
- 130.Puklowski A, Homsi Y, Keller D, May M, Chauhan S, Kossatz U, Grunwald V, Kubicka S, Pich A, Manns MP, Hoffmann I, Gonczy P, Malek NP (2011) The SCF-Fbxw5 E3-ubiquitin ligase is regulated by Plk4 and targets HsSAS-6 to control centrosome duplication. Nat Cell Biol 13:1004–1009PubMedCrossRefGoogle Scholar
- 138.Wheway G, Schmidts M, Mans DA, Szymanska K, Nguyen TM, Racher H, Phelps IG, Toedt G, Kennedy J, Wunderlich KA, Sorusch N, Abdelhamed ZA, Natarajan S, Herridge W, van Reeuwijk J, Horn N, Boldt K, Parry DA, Letteboer SJ, Roosing S, Adams M, Bell SM, Bond J, Higgins J, Morrison EE, Tomlinson DC, Slaats GG, van Dam TJ, Huang L, Kessler K, Giessl A, Logan CV, Boyle EA, Shendure J, Anazi S, Aldahmesh M, Al Hazzaa S, Hegele RA, Ober C, Frosk P, Mhanni AA, Chodirker BN, Chudley AE, Lamont R, Bernier FP, Beaulieu CL, Gordon P, Pon RT, Donahue C, Barkovich AJ, Wolf L, Toomes C, Thiel CT, Boycott KM, McKibbin M, Inglehearn CF, Stewart F, Omran H, Huynen MA, Sergouniotis PI, Alkuraya FS, Parboosingh JS, Innes AM, Willoughby CE, Giles RH, Webster AR, Ueffing M, Blacque O, Gleeson JG, Wolfrum U, Beales PL, Gibson T, Doherty D, Mitchison HM, Roepman R, Johnson CA, UK K Consortium, University of Washington Center for Mendelian, Genomics (2015) An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes. Nat Cell Biol 17:1074–1087PubMedPubMedCentralCrossRefGoogle Scholar
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