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Cells Jun 2020Centrioles are microtubule-based cellular structures present in most human cells that build centrosomes and cilia. Proliferating cells have only two centrosomes and this... (Review)
Review
Centrioles are microtubule-based cellular structures present in most human cells that build centrosomes and cilia. Proliferating cells have only two centrosomes and this number is stringently maintained through the temporally and spatially controlled processes of centriole assembly and segregation. The assembly of new centrioles begins in early S phase and ends in the third G1 phase from their initiation. This lengthy process of centriole assembly from their initiation to their maturation is characterized by numerous structural and still poorly understood biochemical changes, which occur in synchrony with the progression of cells through three consecutive cell cycles. As a result, proliferating cells contain three structurally, biochemically, and functionally distinct types of centrioles: procentrioles, daughter centrioles, and mother centrioles. This age difference is critical for proper centrosome and cilia function. Here we discuss the centriole assembly process as it occurs in somatic cycling human cells with a focus on the structural, biochemical, and functional characteristics of centrioles of different ages.
Topics: Aging; Centrioles; Centrosome; Humans
PubMed: 32526902
DOI: 10.3390/cells9061429 -
Cell Reports Jun 2018The number of centrioles is tightly controlled to ensure bipolar spindle assembly, which is a prerequisite to maintain genome integrity. However, our understanding of...
The number of centrioles is tightly controlled to ensure bipolar spindle assembly, which is a prerequisite to maintain genome integrity. However, our understanding of the fundamental principle that governs the formation of a single procentriole per parental centriole is incomplete. Here, we show that the local restriction of Plk4, a master regulator of the procentriole formation, is achieved by a bimodal interaction of STIL with Plk4. We demonstrate that the conserved short coiled-coil region of STIL binds to and protects Plk4 from protein degradation at the site of procentriole formation. On the other hand, the conserved C-terminal region of STIL named truncated in microcephaly (TIM) domain promotes autophosphorylation and degradation of adjacent Plk4 by the direct interaction. Thus, we propose that positive and negative regulation based on the bimodal binding of Plk4 and STIL ensures the formation of a single procentriole per parental centriole.
Topics: 3' Untranslated Regions; Amino Acid Motifs; Animals; Cell Line; Centrioles; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins; Phosphorylation; Protein Binding; Protein Domains; Protein Serine-Threonine Kinases; RNA Interference; RNA, Small Interfering; Sequence Alignment
PubMed: 29898389
DOI: 10.1016/j.celrep.2018.05.030 -
Current Biology : CB Nov 2014Centrioles are 9-fold symmetrical structures at the core of centrosomes and base of cilia whose dysfunction has been linked to a wide range of inherited diseases and...
Centrioles are 9-fold symmetrical structures at the core of centrosomes and base of cilia whose dysfunction has been linked to a wide range of inherited diseases and cancer. Their duplication is regulated by a protein kinase of conserved structure, the C. elegans ZYG-1 or its Polo-like kinase 4 (Plk4) counterpart in other organisms. Although Plk4's centriolar partners and mechanisms that regulate its stability are known, its crucial substrates for centriole duplication have never been identified. Here we show that Drosophila Plk4 phosphorylates four conserved serines in the STAN motif of the core centriole protein Ana2 to enable it to bind and recruit its Sas6 partner. Ana2 and Sas6 normally load onto both mother and daughter centrioles immediately after their disengagement toward the end of mitosis to seed procentriole formation. Nonphosphorylatable Ana2 still localizes to the centriole but can no longer recruit Sas6 and centriole duplication fails. Thus, following centriole disengagement, recruitment of Ana2 and its phosphorylation by Plk4 are the earliest known events in centriole duplication to recruit Sas6 and thereby establish the architecture of the new procentriole engaged with its parent.
Topics: Amino Acid Sequence; Animals; Cell Cycle Proteins; Centrioles; Drosophila; Drosophila Proteins; Microtubule-Associated Proteins; Molecular Sequence Data; Phosphorylation; Protein Serine-Threonine Kinases; Sequence Alignment
PubMed: 25264260
DOI: 10.1016/j.cub.2014.08.061 -
The EMBO Journal May 2010Centrosomes are cellular organelles that have a major role in the spatial organisation of the microtubule network. The centrosome is comprised of two centrioles that...
Centrosomes are cellular organelles that have a major role in the spatial organisation of the microtubule network. The centrosome is comprised of two centrioles that duplicate only once during the cell cycle, generating a procentriole from each mature centriole. Despite the essential roles of centrosomes, the detailed structural mechanisms involved in centriole duplication remain largely unknown. Here, we describe human procentriole assembly using cryo-electron tomography. In centrosomes, isolated from human lymphoblasts, we observed that each one of the nine microtubule triplets grows independently around a periodic central structure. The proximal end of the A-microtubule is capped by a conical structure and the B- and C-microtubules elongate bidirectionally from its wall. These observations suggest that the gamma tubulin ring complex (gamma-TuRC) has a fundamental role in procentriole formation by nucleating the A-microtubule that acts as a template for B-microtubule elongation that, in turn, supports C-microtubule growth. This study provides new insights into the initial structural events involved in procentriole assembly and establishes the basis for determining the molecular mechanisms of centriole duplication on the nanometric scale.
Topics: Cell Line; Centrioles; Electron Microscope Tomography; Humans; Lymphocytes; Microtubules; Models, Biological; Tubulin
PubMed: 20339347
DOI: 10.1038/emboj.2010.45 -
The EMBO Journal Nov 2022Over the course of evolution, the centrosome function has been conserved in most eukaryotes, but its core architecture has evolved differently in some clades, with the...
Over the course of evolution, the centrosome function has been conserved in most eukaryotes, but its core architecture has evolved differently in some clades, with the presence of centrioles in humans and a spindle pole body (SPB) in yeast. Similarly, the composition of these two core elements has diverged, with the exception of Centrin and SFI1, which form a complex in yeast to initiate SPB duplication. However, it remains unclear whether this complex exists at centrioles and whether its function has been conserved. Here, using expansion microscopy, we demonstrate that human SFI1 is a centriolar protein that associates with a pool of Centrin at the distal end of the centriole. We also find that both proteins are recruited early during procentriole assembly and that depletion of SFI1 results in the loss of the distal pool of Centrin, without altering centriole duplication. Instead, we show that SFI1/Centrin complex is essential for centriolar architecture, CEP164 distribution, and CP110 removal during ciliogenesis. Together, our work reveals a conserved SFI1/Centrin module displaying divergent functions between mammals and yeast.
Topics: Animals; Humans; Cell Cycle Proteins; Centrioles; Repressor Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Spindle Pole Bodies; Calcium-Binding Proteins
PubMed: 36125182
DOI: 10.15252/embj.2022112107 -
Nature Communications Mar 2024HIV-1 infection elevates the risk of developing various cancers, including T-cell lymphoma. Whether HIV-1-encoded proteins directly contribute to oncogenesis remains...
HIV-1 infection elevates the risk of developing various cancers, including T-cell lymphoma. Whether HIV-1-encoded proteins directly contribute to oncogenesis remains unknown. We observe that approximately 1-5% of CD4 T cells from the blood of people living with HIV-1 exhibit over-duplicated centrioles, suggesting that centrosome amplification underlies the development of HIV-1-associated cancers by driving aneuploidy. Through affinity purification, biochemical, and cellular analyses, we discover that Vpr, an accessory protein of HIV-1, hijacks the centriole duplication machinery and induces centrosome amplification and aneuploidy. Mechanistically, Vpr forms a cooperative ternary complex with an E3 ligase subunit, VprBP, and polo-like kinase 4 (Plk4). Unexpectedly, however, the complex enhances Plk4's functionality by promoting its relocalization to the procentriole assembly and induces centrosome amplification. Loss of either Vpr's C-terminal 17 residues or VprBP acidic region, the two elements required for binding to Plk4 cryptic polo-box, abrogates Vpr's capacity to induce these events. Furthermore, HIV-1 WT, but not its Vpr mutant, induces multiple centrosomes and aneuploidy in human primary CD4 T cells. We propose that the Vpr•VprBP•Plk4 complex serves as a molecular link that connects HIV-1 infection to oncogenesis and that inhibiting the Vpr C-terminal motif may reduce the occurrence of HIV-1-associated cancers.
Topics: Humans; T-Lymphocytes; HIV-1; Centrosome; Carcinogenesis; Cell Transformation, Neoplastic; Aneuploidy; CD4-Positive T-Lymphocytes
PubMed: 38443376
DOI: 10.1038/s41467-024-46306-8 -
IScience Oct 2018Centrioles, the cores of centrosomes and cilia, duplicate every cell cycle to ensure their faithful inheritance. How only a single procentriole is produced on each...
Centrioles, the cores of centrosomes and cilia, duplicate every cell cycle to ensure their faithful inheritance. How only a single procentriole is produced on each mother centriole remains enigmatic. We propose the first mechanistic biophysical model for procentriole initiation which posits that interactions between kinase PLK4 and its activator-substrate STIL are central for procentriole initiation. The model recapitulates the transition from a uniform "ring" of PLK4 surrounding the mother centriole to a single PLK4 "spot" that initiates procentriole assembly. This symmetry breaking requires autocatalytic activation of PLK4 and enhanced centriolar anchoring of PLK4 by phosphorylated STIL. We find that in situ degradation of active PLK4 cannot break symmetry. The model predicts that competition between transient PLK4 activity maxima for PLK4-STIL complexes destabilizes the PLK4 ring and produces instead a single PLK4 spot. Weakening of competition by overexpression of PLK4 and STIL causes progressive addition of supernumerary procentrioles, as observed experimentally.
PubMed: 30340068
DOI: 10.1016/j.isci.2018.10.003 -
Biology Open Aug 2018The centrosome is the organizing center of microtubules in the cell, the basis for the origin of cilia and flagella and a site for the concentration of a regulatory...
The centrosome is the organizing center of microtubules in the cell, the basis for the origin of cilia and flagella and a site for the concentration of a regulatory proteins multitude. The centrosome comprises two centrioles surrounded by pericentriolar material. Centrioles in the cells of different organisms can contain nine triplets, doublets or singlets of microtubules. Here, we show that in somatic cells of male wasp larvae , centrioles do not contain microtubules and are composed of nine electron-dense prongs, which together form a cogwheel structure. These microtubule-free centrioles can be the platform for procentriole formation and form microtubule-free cilia-like structures. In nymph and imago cells centrioles have a microtubule triplet structure. Our study describes how centriole structure differs in a development-stage-dependent and a cell-type-dependent manner. The discovery of a centriole without microtubules casts a new light on the centriole formation process and the evolution of this organelle.
PubMed: 29997243
DOI: 10.1242/bio.036012 -
Developmental Cell Aug 2007Centrosome duplication involves the formation of a single procentriole next to each centriole, once per cell cycle. The mechanisms governing procentriole formation and...
Centrosome duplication involves the formation of a single procentriole next to each centriole, once per cell cycle. The mechanisms governing procentriole formation and those restricting its occurrence to one event per centriole are poorly understood. Here, we show that HsSAS-6 is necessary for procentriole formation and that it localizes asymmetrically next to the centriole at the onset of procentriole formation. HsSAS-6 levels oscillate during the cell cycle, with the protein being degraded in mitosis and starting to accumulate again at the end of the following G1. Our findings indicate that APC(Cdh1) targets HsSAS-6 for degradation by the 26S proteasome. Importantly, we demonstrate that increased HsSAS-6 levels promote formation of more than one procentriole per centriole. Therefore, regulated HsSAS-6 levels normally ensure that each centriole seeds the formation of a single procentriole per cell cycle, thus playing a fundamental role in driving the centrosome duplication cycle and ensuring genome integrity.
Topics: Anaphase; Cell Cycle; Cell Cycle Proteins; Centrioles; HeLa Cells; Humans; Models, Biological; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport
PubMed: 17681132
DOI: 10.1016/j.devcel.2007.07.004 -
Current Biology : CB Jun 2009The centrosome is the principal microtubule organizing center (MTOC) of animal cells. Accurate centrosome duplication is fundamental for genome integrity and entails the...
The centrosome is the principal microtubule organizing center (MTOC) of animal cells. Accurate centrosome duplication is fundamental for genome integrity and entails the formation of one procentriole next to each existing centriole, once per cell cycle. The procentriole then elongates to eventually reach the same size as the centriole. The mechanisms that govern elongation of the centriolar cylinder and their potential relevance for cell division are not known. Here, we show that the SAS-4-related protein CPAP is required for centrosome duplication in cycling human cells. Furthermore, we demonstrate that CPAP overexpression results in the formation of abnormally long centrioles. This also promotes formation of more than one procentriole in the vicinity of such overly long centrioles, eventually resulting in the presence of supernumerary MTOCs. This in turn leads to multipolar spindle assembly and cytokinesis defects. Overall, our findings suggest that centriole length must be carefully regulated to restrict procentriole number and thus ensure accurate cell division.
Topics: Animals; Cell Cycle; Cell Division; Cell Line; Centrioles; Humans; Microtubule-Associated Proteins; Recombinant Fusion Proteins; Spindle Apparatus
PubMed: 19481460
DOI: 10.1016/j.cub.2009.05.018