RESUMO
Bidirectional transport in cilia is carried out by polymers of the IFTA and IFTB protein complexes, called anterograde and retrograde intraflagellar transport (IFT) trains. Anterograde trains deliver cargoes from the cell to the cilium tip, then convert into retrograde trains for cargo export. We set out to understand how the IFT complexes can perform these two directly opposing roles before and after conversion. We use cryoelectron tomography and in situ cross-linking mass spectrometry to determine the structure of retrograde IFT trains and compare it with the known structure of anterograde trains. The retrograde train is a 2-fold symmetric polymer organized around a central thread of IFTA complexes. We conclude that anterograde-to-retrograde remodeling involves global rearrangements of the IFTA/B complexes and requires complete disassembly of the anterograde train. Finally, we describe how conformational changes to cargo-binding sites facilitate unidirectional cargo transport in a bidirectional system.
RESUMO
Mastigonemes, the hair-like lateral appendages lining cilia or flagella, participate in mechanosensation and cellular motion, but their constituents and structure have remained unclear. Here, we report the cryo-EM structure of native mastigonemes isolated from Chlamydomonas at 3.0 Å resolution. The long stem assembles as a super spiral, with each helical turn comprising four pairs of anti-parallel mastigoneme-like protein 1 (Mst1). A large array of arabinoglycans, which represents a common class of glycosylation in plants and algae, is resolved surrounding the type II poly-hydroxyproline (Hyp) helix in Mst1. The EM map unveils a mastigoneme axial protein (Mstax) that is rich in heavily glycosylated Hyp and contains a PKD2-like transmembrane domain (TMD). Mstax, with nearly 8,000 residues spanning from the intracellular region to the distal end of the mastigoneme, provides the framework for Mst1 assembly. Our study provides insights into the complexity of protein and glycan interactions in native bio-architectures.
Assuntos
Chlamydomonas , Cílios , Chlamydomonas/citologia , Cílios/química , Cílios/ultraestrutura , Flagelos , Polissacarídeos , ProteínasRESUMO
Hydroxyproline-rich glycoproteins (HRGPs) are a ubiquitous class of protein in the extracellular matrices and cell walls of plants and algae, yet little is known of their native structures or interactions. Here, we used electron cryomicroscopy (cryo-EM) to determine the structure of the hydroxyproline-rich mastigoneme, an extracellular filament isolated from the cilia of the alga Chlamydomonas reinhardtii. The structure demonstrates that mastigonemes are formed from two HRGPs (a filament of MST1 wrapped around a single copy of MST3) that both have hyperglycosylated poly(hydroxyproline) helices. Within the helices, O-linked glycosylation of the hydroxyproline residues and O-galactosylation of interspersed serine residues create a carbohydrate casing. Analysis of the associated glycans reveals how the pattern of hydroxyproline repetition determines the type and extent of glycosylation. MST3 possesses a PKD2-like transmembrane domain that forms a heteromeric polycystin-like cation channel with PKD2 and SIP, explaining how mastigonemes are tethered to ciliary membranes.
Assuntos
Chlamydomonas reinhardtii , Cílios , Glicoproteínas , Cílios/química , Glicoproteínas/química , Glicosilação , Hidroxiprolina/química , Plantas/metabolismo , Chlamydomonas reinhardtii/químicaRESUMO
Sperm motility is crucial to reproductive success in sexually reproducing organisms. Impaired sperm movement causes male infertility, which is increasing globally. Sperm are powered by a microtubule-based molecular machine-the axoneme-but it is unclear how axonemal microtubules are ornamented to support motility in diverse fertilization environments. Here, we present high-resolution structures of native axonemal doublet microtubules (DMTs) from sea urchin and bovine sperm, representing external and internal fertilizers. We identify >60 proteins decorating sperm DMTs; at least 15 are sperm associated and 16 are linked to infertility. By comparing DMTs across species and cell types, we define core microtubule inner proteins (MIPs) and analyze evolution of the tektin bundle. We identify conserved axonemal microtubule-associated proteins (MAPs) with unique tubulin-binding modes. Additionally, we identify a testis-specific serine/threonine kinase that links DMTs to outer dense fibers in mammalian sperm. Our study provides structural foundations for understanding sperm evolution, motility, and dysfunction at a molecular level.
Assuntos
Motilidade dos Espermatozoides , Cauda do Espermatozoide , Masculino , Animais , Bovinos , Cauda do Espermatozoide/química , Cauda do Espermatozoide/metabolismo , Sêmen , Microtúbulos/metabolismo , Axonema/química , Espermatozoides , MamíferosRESUMO
How SARS-CoV-2 penetrates the airway barrier of mucus and periciliary mucins to infect nasal epithelium remains unclear. Using primary nasal epithelial organoid cultures, we found that the virus attaches to motile cilia via the ACE2 receptor. SARS-CoV-2 traverses the mucus layer, using motile cilia as tracks to access the cell body. Depleting cilia blocks infection for SARS-CoV-2 and other respiratory viruses. SARS-CoV-2 progeny attach to airway microvilli 24 h post-infection and trigger formation of apically extended and highly branched microvilli that organize viral egress from the microvilli back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Phosphoproteomics and kinase inhibition reveal that microvillar remodeling is regulated by p21-activated kinases (PAK). Importantly, Omicron variants bind with higher affinity to motile cilia and show accelerated viral entry. Our work suggests that motile cilia, microvilli, and mucociliary-dependent mucus flow are critical for efficient virus replication in nasal epithelia.
Assuntos
COVID-19 , Sistema Respiratório , SARS-CoV-2 , Humanos , Cílios/fisiologia , Cílios/virologia , COVID-19/virologia , Sistema Respiratório/citologia , Sistema Respiratório/virologia , SARS-CoV-2/fisiologia , Microvilosidades/fisiologia , Microvilosidades/virologia , Internalização do Vírus , Células Epiteliais/fisiologia , Células Epiteliais/virologiaRESUMO
Intraflagellar transport (IFT) trains are massive molecular machines that traffic proteins between cilia and the cell body. Each IFT train is a dynamic polymer of two large complexes (IFT-A and -B) and motor proteins, posing a formidable challenge to mechanistic understanding. Here, we reconstituted the complete human IFT-A complex and obtained its structure using cryo-EM. Combined with AlphaFold prediction and genome-editing studies, our results illuminate how IFT-A polymerizes, interacts with IFT-B, and uses an array of ß-propeller and TPR domains to create "carriages" of the IFT train that engage TULP adaptor proteins. We show that IFT-Aâ TULP carriages are essential for cilia localization of diverse membrane proteins, as well as ICK-the key kinase regulating IFT train turnaround. These data establish a structural link between IFT-A's distinct functions, provide a blueprint for IFT-A in the train, and shed light on how IFT evolved from a proto-coatomer ancestor.
Assuntos
Cílios , Cinesinas , Humanos , Cílios/metabolismo , Transporte Biológico , Cinesinas/metabolismo , Dineínas/metabolismo , Proteínas de Membrana/metabolismo , Transporte Proteico , Flagelos/metabolismoRESUMO
Intraflagellar transport (IFT) is the highly conserved process by which proteins are transported along ciliary microtubules by a train-like polymeric assembly of IFT-A and IFT-B complexes. IFT-A is sandwiched between IFT-B and the ciliary membrane, consistent with its putative role in transporting transmembrane and membrane-associated cargoes. Here, we have used single-particle analysis electron cryomicroscopy (cryo-EM) to determine structures of native IFT-A complexes. We show that subcomplex rearrangements enable IFT-A to polymerize laterally on anterograde IFT trains, revealing a cooperative assembly mechanism. Surprisingly, we discover that binding of IFT-A to IFT-B shields the preferred lipid-binding interface from the ciliary membrane but orients an interconnected network of ß-propeller domains with the capacity to accommodate diverse cargoes toward the ciliary membrane. This work provides a mechanistic basis for understanding IFT-train assembly and cargo interactions.
Assuntos
Cílios , Proteínas , Polimerização , Transporte Biológico , Cílios/metabolismo , Proteínas/metabolismo , Microtúbulos/metabolismo , Flagelos/metabolismo , Transporte ProteicoRESUMO
Chemical synapses between axons and dendrites mediate neuronal intercellular communication. Here, we describe a synapse between axons and primary cilia: the axo-ciliary synapse. Using enhanced focused ion beam-scanning electron microscopy on samples with optimally preserved ultrastructure, we discovered synapses between brainstem serotonergic axons and the primary cilia of hippocampal CA1 pyramidal neurons. Functionally, these cilia are enriched in a ciliary-restricted serotonin receptor, the 5-hydroxytryptamine receptor 6 (5-HTR6). Using a cilia-targeted serotonin sensor, we show that opto- and chemogenetic stimulation of serotonergic axons releases serotonin onto cilia. Ciliary 5-HTR6 stimulation activates a non-canonical Gαq/11-RhoA pathway, which modulates nuclear actin and increases histone acetylation and chromatin accessibility. Ablation of this pathway reduces chromatin accessibility in CA1 pyramidal neurons. As a signaling apparatus with proximity to the nucleus, axo-ciliary synapses short circuit neurotransmission to alter the postsynaptic neuron's epigenetic state.
Assuntos
Axônios/fisiologia , Cromatina/química , Cílios , Sinapses , Núcleo Celular/metabolismo , Cromatina/metabolismo , Cílios/metabolismo , Hipocampo/citologia , Hipocampo/fisiologia , Serotonina/metabolismo , Transdução de Sinais , Sinapses/fisiologiaRESUMO
Hedgehog pathway components and select G protein-coupled receptors (GPCRs) localize to the primary cilium, an organelle specialized for signal transduction. We investigated whether cells distinguish between ciliary and extraciliary GPCR signaling. To test whether ciliary and extraciliary cyclic AMP (cAMP) convey different information, we engineered optogenetic and chemogenetic tools to control the subcellular site of cAMP generation. Generating equal amounts of ciliary and cytoplasmic cAMP in zebrafish and mammalian cells revealed that ciliary cAMP, but not cytoplasmic cAMP, inhibited Hedgehog signaling. Modeling suggested that the distinct geometries of the cilium and cell body differentially activate local effectors. The search for effectors identified a ciliary pool of protein kinase A (PKA). Blocking the function of ciliary PKA, but not extraciliary PKA, activated Hedgehog signal transduction and reversed the effects of ciliary cAMP. Therefore, cells distinguish ciliary and extraciliary cAMP using functionally and spatially distinct pools of PKA, and different subcellular pools of cAMP convey different information.
Assuntos
Cílios/metabolismo , AMP Cíclico/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Linhagem Celular , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citoplasma/metabolismo , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Neurônios/metabolismo , Optogenética/métodos , Transdução de Sinais/fisiologia , Peixe-Zebra/metabolismoRESUMO
Cilia are ubiquitous microtubule-based eukaryotic organelles that project from the cell to generate motility or function in cellular signaling. Motile cilia or flagella contain axonemal dynein motors and other complexes to achieve beating. Primary cilia are immotile and act as signaling hubs, with receptors shuttling between the cytoplasm and ciliary compartment. In both cilia types, an intraflagellar transport (IFT) system powered by unique kinesin and dynein motors functions to deliver the molecules required to build cilia and maintain their functions. Cryo-electron tomography has helped to reveal the organization of protein complex arrangement along the axoneme and the structure of anterograde IFT trains as well as the structure of primary cilia. Only recently, single-particle analysis (SPA) cryo-electron microscopy has provided molecular details of the protein organization of ciliary components, helping us to understand how they bind to microtubule doublets and how mechanical force propagated by dynein conformational changes is converted into ciliary beating. Here we highlight recent structural advances that are leading to greater knowledge of ciliary function.
Assuntos
Dineínas do Axonema , Cílios , Dineínas do Axonema/genética , Dineínas do Axonema/metabolismo , Transporte Biológico/fisiologia , Biologia , Cílios/metabolismo , Microscopia Crioeletrônica , Flagelos/metabolismo , CinesinasRESUMO
The centriole is an ancient microtubule-based organelle with a conserved nine-fold symmetry. Centrioles form the core of centrosomes, which organize the interphase microtubule cytoskeleton of most animal cells and form the poles of the mitotic spindle. Centrioles can also be modified to form basal bodies, which template the formation of cilia and play central roles in cellular signaling, fluid movement, and locomotion. In this review, we discuss developments in our understanding of the biogenesis of centrioles and cilia and the regulatory controls that govern their structure and number. We also discuss how defects in these processes contribute to a spectrum of human diseases and how new technologies have expanded our understanding of centriole and cilium biology, revealing exciting avenues for future exploration.
Assuntos
Centríolos/fisiologia , Cílios/patologia , Biogênese de Organelas , Animais , Ciclo Celular , Centríolos/metabolismo , Centríolos/ultraestrutura , Cílios/metabolismo , Cílios/ultraestrutura , Ciliopatias , Eucariotos/citologia , Eucariotos/fisiologia , Humanos , Mitose , Transdução de SinaisRESUMO
The axoneme of motile cilia is the largest macromolecular machine of eukaryotic cells. In humans, impaired axoneme function causes a range of ciliopathies. Axoneme assembly, structure, and motility require a radially arranged set of doublet microtubules, each decorated in repeating patterns with non-tubulin components. We use single-particle cryo-electron microscopy to visualize and build an atomic model of the repeating structure of a native axonemal doublet microtubule, which reveals the identities, positions, repeat lengths, and interactions of 38 associated proteins, including 33 microtubule inner proteins (MIPs). The structure demonstrates how these proteins establish the unique architecture of doublet microtubules, maintain coherent periodicities along the axoneme, and stabilize the microtubules against the repeated mechanical stress induced by ciliary motility. Our work elucidates the architectural principles that underpin the assembly of this large, repetitive eukaryotic structure and provides a molecular basis for understanding the etiology of human ciliopathies.
Assuntos
Axonema/ultraestrutura , Cílios/ultraestrutura , Ciliopatias/patologia , Microtúbulos/ultraestrutura , Axonema/química , Axonema/genética , Movimento Celular/genética , Cílios/química , Cílios/genética , Ciliopatias/genética , Ciliopatias/metabolismo , Microscopia Crioeletrônica , Humanos , Proteínas dos Microtúbulos/química , Proteínas dos Microtúbulos/ultraestrutura , Microtúbulos/química , Microtúbulos/genética , Estresse MecânicoRESUMO
Adult mesenchymal stem cells, including preadipocytes, possess a cellular sensory organelle called the primary cilium. Ciliated preadipocytes abundantly populate perivascular compartments in fat and are activated by a high-fat diet. Here, we sought to understand whether preadipocytes use their cilia to sense and respond to external cues to remodel white adipose tissue. Abolishing preadipocyte cilia in mice severely impairs white adipose tissue expansion. We discover that TULP3-dependent ciliary localization of the omega-3 fatty acid receptor FFAR4/GPR120 promotes adipogenesis. FFAR4 agonists and ω-3 fatty acids, but not saturated fatty acids, trigger mitosis and adipogenesis by rapidly activating cAMP production inside cilia. Ciliary cAMP activates EPAC signaling, CTCF-dependent chromatin remodeling, and transcriptional activation of PPARγ and CEBPα to initiate adipogenesis. We propose that dietary ω-3 fatty acids selectively drive expansion of adipocyte numbers to produce new fat cells and store saturated fatty acids, enabling homeostasis of healthy fat tissue.
Assuntos
Adipogenia , Cílios/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Fator de Ligação a CCCTC/metabolismo , Cromatina/metabolismo , Cílios/efeitos dos fármacos , AMP Cíclico/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/metabolismoRESUMO
The seven-transmembrane-spanning protein Smoothened is the central transducer in Hedgehog signaling, a pathway fundamental in development and in cancer. Smoothened is activated by cholesterol binding to its extracellular cysteine-rich domain (CRD). How this interaction leads to changes in the transmembrane domain and Smoothened activation is unknown. Here, we report crystal structures of sterol-activated Smoothened. The CRD undergoes a dramatic reorientation, allosterically causing the transmembrane domain to adopt a conformation similar to active G-protein-coupled receptors. We show that Smoothened contains a unique inhibitory π-cation lock, which is broken on activation and is disrupted in constitutively active oncogenic mutants. Smoothened activation opens a hydrophobic tunnel, suggesting a pathway for cholesterol movement from the inner membrane leaflet to the CRD. All Smoothened antagonists bind the transmembrane domain and block tunnel opening, but cyclopamine also binds the CRD, inducing the active transmembrane conformation. Together, these results define the mechanisms of Smoothened activation and inhibition.
Assuntos
Proteínas Hedgehog/metabolismo , Receptor Smoothened/química , Proteínas de Xenopus/química , Regulação Alostérica , Animais , Sítios de Ligação , Linhagem Celular , Colesterol/química , Colesterol/metabolismo , Cristalografia por Raios X , Citometria de Fluxo , Proteínas Hedgehog/genética , Humanos , Camundongos , Simulação de Dinâmica Molecular , Ligação Proteica , Domínios Proteicos , Estrutura Terciária de Proteína , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Receptor Smoothened/antagonistas & inibidores , Receptor Smoothened/metabolismo , Alcaloides de Veratrum/química , Alcaloides de Veratrum/metabolismo , Proteínas de Xenopus/antagonistas & inibidores , Proteínas de Xenopus/metabolismo , Xenopus laevis/metabolismoRESUMO
Electron cryotomography (ECT) provides three-dimensional views of macromolecular complexes inside cells in a native frozen-hydrated state. Over the last two decades, ECT has revealed the ultrastructure of cells in unprecedented detail. It has also allowed us to visualize the structures of macromolecular machines in their native context inside intact cells. In many cases, such machines cannot be purified intact for in vitro study. In other cases, the function of a structure is lost outside the cell, so that the mechanism can be understood only by observation in situ. In this review, we describe the technique and its history and provide examples of its power when applied to cell biology. We also discuss the integration of ECT with other techniques, including lower-resolution fluorescence imaging and higher-resolution atomic structure determination, to cover the full scale of cellular processes.
Assuntos
Microscopia Crioeletrônica/métodos , Tomografia com Microscopia Eletrônica/métodos , Fímbrias Bacterianas/ultraestrutura , Poro Nuclear/química , Imagem Óptica/métodos , Células Procarióticas/ultraestrutura , Archaea/metabolismo , Archaea/ultraestrutura , Bactérias/metabolismo , Bactérias/ultraestrutura , Sistemas de Secreção Bacterianos/metabolismo , Sistemas de Secreção Bacterianos/ultraestrutura , Microscopia Crioeletrônica/história , Microscopia Crioeletrônica/instrumentação , Tomografia com Microscopia Eletrônica/história , Tomografia com Microscopia Eletrônica/instrumentação , Fímbrias Bacterianas/metabolismo , Flagelos/metabolismo , Flagelos/ultraestrutura , História do Século XX , História do Século XXI , Modelos Moleculares , Poro Nuclear/metabolismo , Poro Nuclear/ultraestrutura , Imagem Óptica/história , Imagem Óptica/instrumentação , Células Procarióticas/metabolismo , Domínios Proteicos , Estrutura Secundária de ProteínaRESUMO
Signaling receptors dynamically exit cilia upon activation of signaling pathways such as Hedgehog. Here, we find that when activated G protein-coupled receptors (GPCRs) fail to undergo BBSome-mediated retrieval from cilia back into the cell, these GPCRs concentrate into membranous buds at the tips of cilia before release into extracellular vesicles named ectosomes. Unexpectedly, actin and the actin regulators drebrin and myosin 6 mediate ectosome release from the tip of cilia. Mirroring signal-dependent retrieval, signal-dependent ectocytosis is a selective and effective process that removes activated signaling molecules from cilia. Congruently, ectocytosis compensates for BBSome defects as ectocytic removal of GPR161, a negative regulator of Hedgehog signaling, permits the appropriate transduction of Hedgehog signals in Bbs mutants. Finally, ciliary receptors that lack retrieval determinants such as the anorexigenic GPCR NPY2R undergo signal-dependent ectocytosis in wild-type cells. Our data show that signal-dependent ectocytosis regulates ciliary signaling in physiological and pathological contexts.
Assuntos
Cílios/metabolismo , Vesículas Extracelulares/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Actinas/metabolismo , Animais , Linhagem Celular , Humanos , Rim/citologia , Rim/metabolismo , Camundongos , Microscopia Eletrônica de Varredura , Receptores de Somatostatina/metabolismo , Transdução de SinaisRESUMO
The life cycle of a primary cilium begins in quiescence and ends prior to mitosis. In quiescent cells, the primary cilium insulates itself from contiguous dynamic membrane processes on the cell surface to function as a stable signaling apparatus. Here, we demonstrate that basal restriction of ciliary structure dynamics is established by the cilia-enriched phosphoinositide 5-phosphatase, Inpp5e. Growth induction displaces ciliary Inpp5e and accumulates phosphatidylinositol 4,5-bisphosphate in distal cilia. This change triggers otherwise-forbidden actin polymerization in primary cilia, which excises cilia tips in a process we call cilia decapitation. While cilia disassembly is traditionally thought to occur solely through resorption, we show that an acute loss of IFT-B through cilia decapitation precedes resorption. Finally, we propose that cilia decapitation induces mitogenic signaling and constitutes a molecular link between the cilia life cycle and cell-division cycle. This newly defined ciliary mechanism may find significance in cell proliferation control during normal development and cancer.
Assuntos
Ciclo Celular , Cílios/metabolismo , Actinas/metabolismo , Animais , Rim/citologia , Rim/metabolismo , Camundongos , Células NIH 3T3 , Fosfatidilinositol 4,5-Difosfato , Monoéster Fosfórico Hidrolases/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismoRESUMO
The Integrator complex attenuates gene expression via the premature termination of RNA polymerase II (RNAP2) at promoter-proximal pausing sites. It is required for stimulus response, cell differentiation, and neurodevelopment, but how gene-specific and adaptive regulation by Integrator is achieved remains unclear. Here, we identify two sites on human Integrator subunits 13/14 that serve as binding hubs for sequence-specific transcription factors (TFs) and other transcription effector complexes. When Integrator is attached to paused RNAP2, these hubs are positioned upstream of the transcription bubble, consistent with simultaneous TF-promoter tethering. The TFs co-localize with Integrator genome-wide, increase Integrator abundance on target genes, and co-regulate responsive transcriptional programs. For instance, sensory cilia formation induced by glucose starvation depends on Integrator-TF contacts. Our data suggest TF-mediated promoter recruitment of Integrator as a widespread mechanism for targeted transcription regulation.
Assuntos
Regulação da Expressão Gênica , Regiões Promotoras Genéticas , RNA Polimerase II , Fatores de Transcrição , Transcrição Gênica , Humanos , RNA Polimerase II/metabolismo , RNA Polimerase II/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Sítios de Ligação , Ligação Proteica , Células HEK293 , Cílios/metabolismo , Cílios/genéticaRESUMO
Here I discuss the study in this issue of Genes & Development by Youn et al. (pp. 737-751), which describes defined and diverse roles of primary cilia in molecularly distinct medulloblastoma subgroups, highlighting once again the importance of designing subgroup-specific therapeutic approaches for this tumor.
Assuntos
Neoplasias Cerebelares , Meduloblastoma , Neoplasias Cerebelares/genética , Cílios/genética , Humanos , Meduloblastoma/genéticaRESUMO
The primary cilium, a signaling organelle projecting from the surface of a cell, controls cellular physiology and behavior. The presence or absence of primary cilia is a distinctive feature of a given tumor type; however, whether and how the primary cilium contributes to tumorigenesis are unknown for most tumors. Medulloblastoma (MB) is a common pediatric brain cancer comprising four groups: SHH, WNT, group 3 (G3), and group 4 (G4). From 111 cases of MB, we show that primary cilia are abundant in SHH and WNT MBs but rare in G3 and G4 MBs. Using WNT and G3 MB mouse models, we show that primary cilia promote WNT MB by facilitating translation of mRNA encoding ß-catenin, a major oncoprotein driving WNT MB, whereas cilium loss promotes G3 MB by disrupting cell cycle control and destabilizing the genome. Our findings reveal tumor type-specific ciliary functions and underlying molecular mechanisms. Moreover, we expand the function of primary cilia to translation control and reveal a molecular mechanism by which cilia regulate cell cycle progression, thereby providing new frameworks for studying cilium function in normal and pathologic conditions.