Dynamic Remodeling of Membrane Composition Drives Cell Cycle through Primary Cilia Excision

Phua, Siew Cheng; Chiba, Shuhei; Suzuki, Masako; Su, Emily J.; Roberson, Elle C.; Pusapati, Ganesh V.; Setou, Mitsutoshi; Rohatgi, Rajat; Reiter, Jeremy F.; Ikegami, Koji; Inoue, Takanari

doi:10.1016/j.cell.2016.12.032

Cited by 283 publications

(282 citation statements)

References 61 publications

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“…In addition, the ciliary gate itself has been shown to be dynamic in terms of migrating along the axoneme during Drosophila spermatogenesis [7], and turnover of gate components may facilitate this migration event. Finally, given then ability of cilia to shed ectosomes from their tips [46–50], gating/sorting mechanisms likely exist at both the base and the tip of cilia that together regulate the protein and lipid content of the organelle.…”

Section: Discussionmentioning

confidence: 99%

Protein Interaction Analysis Provides a Map of the Spatial and Temporal Organization of the Ciliary Gating Zone

et al. 2017

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SUMMARY The motility and signaling functions of the primary cilium require a unique protein and lipid composition that is determined by gating mechanisms localized at the base of the cilium. Several protein complexes localize to the gating zone and may regulate ciliary protein composition, however, the mechanisms of ciliary gating and the dynamics of the gating components are largely unknown. Here we used the BiFC (bimolecular fluorescence complementation) assay and report for the first time on the protein-protein interactions that occur between ciliary gating components and transiting cargoes during ciliary entry. We find that the nucleoporin Nup62 and the C-termini of the nephronophthisis (NPHP) proteins NPHP4 and NPHP5 interact with the axoneme-associated kinesin-2 motor KIF17 and thus spatially map to the inner region of the ciliary gating zone. Nup62 and NPHP4 exhibit rapid turnover at the transition zone and thus define dynamic components of the gate. We find that B9D1, AHI1 and the N-termini of NPHP4 and NPHP5 interact with the transmembrane protein SSTR3 and thus spatially map to the outer region of the ciliary gating zone. B9D1, AHI1 and NPHP5 exhibit little to no turnover at the transition zone and thus define components of a stable gating structure. These data provide the first comprehensive map of the molecular orientations of gating zone components along the inner-to-outer axis of the ciliary gating zone. These results advance our understanding of the functional roles of gating zone components in regulating ciliary protein composition.

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Section: Discussionmentioning

confidence: 99%

Protein Interaction Analysis Provides a Map of the Spatial and Temporal Organization of the Ciliary Gating Zone

et al. 2017

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“…Actin-binding proteins in cilia Priyanka Kohli et al formation [63,64]. Moreover, actin networks that transmit tension via the centrosome might also link any mechanical stimuli from the cilium to the actin cytoskeleton in the cell and might therefore be a link between mechanical ciliary bending and polarity signaling.…”

Section: Embo Reportsmentioning

confidence: 99%

The ciliary membrane‐associated proteome reveals actin‐binding proteins as key components of cilia

et al. 2017

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Primary cilia are sensory, antennae-like organelles present on the surface of many cell types. They have been involved in a variety of diseases collectively termed ciliopathies. As cilia are essential regulators of cell signaling, the composition of the ciliary membrane needs to be strictly regulated. To understand regulatory processes at the ciliary membrane, we report the targeting of a genetically engineered enzyme specifically to the ciliary membrane to allow biotinylation and identification of the membrane-associated proteome. Bioinformatic analysis of the comprehensive dataset reveals high-stoichiometric presence of actin-binding proteins inside the cilium. Immunofluorescence stainings and complementary interaction proteomic analyses confirm these findings. Depolymerization of branched F-actin causes further enrichment of the actin-binding and actin-related proteins in cilia, including Myosin 5a (Myo5a). Interestingly, Myo5a knockout decreases ciliation while enhanced levels of Myo5a are observed in cilia upon induction of ciliary disassembly. In summary, we present a novel approach to investigate dynamics of the ciliary membrane proteome in mammalian cells and identify actin-binding proteins as mechanosensitive components of cilia that might have important functions in cilia membrane dynamics.

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“…Similar to photoreceptor cells, cultured mammalian cells generate ECVs from their ciliary tips [103,171]. As Actin filaments are not prominent features in the cilium, it is a surprise that Actin-dependent events are deployed within the cilium to release ciliary ECVs from the tip.…”

Section: Ciliary-derived Vesicles Participate In Diverse Cellular Funmentioning

confidence: 99%

“…Parallel live imaging studies have shown that intraciliary PI(4,5)P 2 and F-actin trigger ECV release from the ciliary tip to promote ciliary disassembly [171]. Thus, cilia-derived ECVs may also prepare for ciliary disassembly, an event that must occur before the initiation of mitosis so that the basal body can relocalize to the spindle pole.…”

Section: Ciliary-derived Vesicles Participate In Diverse Cellular Funmentioning

confidence: 99%

“…Thus, cilia-derived ECVs may also prepare for ciliary disassembly, an event that must occur before the initiation of mitosis so that the basal body can relocalize to the spindle pole. A non-mutually exclusive role for ECV release may therefore be to rapidly discard ciliary membrane and proteins to facilitate ciliary disassembly in preparation for mitosis [171]. …”

Section: Ciliary-derived Vesicles Participate In Diverse Cellular Funmentioning

confidence: 99%

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How the Ciliary Membrane Is Organized Inside-Out to Communicate Outside-In

2018

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Cilia, organelles that move to execute functions like fertilization and signal to execute functions like photoreception and embryonic patterning, are composed of a core of nine-fold doublet microtubules overlain by a membrane. Distinct types of cilia display distinct membrane morphologies, ranging from simple domed cylinders to the highly ornate invaginations and membrane disks of photoreceptor outer segments. Critical for the ability of cilia to signal, both the protein and the lipid compositions of ciliary membranes are different from those of other cellular membranes. This specialization presents a unique challenge for the cell as, unlike membrane-bounded organelles, the ciliary membrane is contiguous with the surrounding plasma membrane. This distinct ciliary membrane is generated in concert with multiple membrane remodeling events that comprise the process of ciliogenesis. Once the cilium is formed, control of ciliary membrane composition relies on discrete molecular machines, including a barrier to membrane proteins entering the cilium at a specialized region of the base of the cilium called the transition zone and a trafficking adaptor that controls G protein-coupled receptor (GPCR) localization to the cilium called the BBSome. The ciliary membrane can be further remodeled by the removal of membrane proteins by the release of ciliary extracellular vesicles that may function in intercellular communication, removal of unneeded proteins or ciliary disassembly. Here, we review the structures and transport mechanisms that control ciliary membrane composition, and discuss how membrane specialization enables the cilium to function as the antenna of the cell.

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Dynamic Remodeling of Membrane Composition Drives Cell Cycle through Primary Cilia Excision

Cited by 283 publications

References 61 publications

Protein Interaction Analysis Provides a Map of the Spatial and Temporal Organization of the Ciliary Gating Zone

Protein Interaction Analysis Provides a Map of the Spatial and Temporal Organization of the Ciliary Gating Zone

The ciliary membrane‐associated proteome reveals actin‐binding proteins as key components of cilia

How the Ciliary Membrane Is Organized Inside-Out to Communicate Outside-In

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