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- Ye Tian: Surveilling stress to live longer
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Authors: Morgado-Palacin L.
First page: e202108098
Abstract: Ye Tian investigates how mitochondrial stress signaling pathways regulate longevity using C. elegans as a model system.
PubDate: Tue, 14 Sep 2021 00:00:00 GMT
DOI: 10.1083/jcb.202108098
Issue No: Vol. 220, No. 10 (2021)
- A polarized anchor for hematopoietic stem cells: Synapse between stem
cells and their niche'-
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Authors: Lee Y; Ding L.
First page: e202108031
Abstract: Multipotent hematopoietic stem cells are maintained by the bone marrow niche, but how niche-derived membrane-bound stem cell factor (mSCF) regulates HSCs remains unclear. In this issue, Hao et al. (2021. J. Cell Biol.https://doi.org/10.1083/jcb.202010118) describe that mSCF, synergistically with VCAM-1, induces large, polarized protrusions that serve as anchors for HSCs to their niche.
PubDate: Mon, 13 Sep 2021 00:00:00 GMT
DOI: 10.1083/jcb.202108031
Issue No: Vol. 220, No. 10 (2021)
- Rab35 controls formation of luminal projections required for bile
canalicular morphogenesis-
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Authors: Cozmescu C; Gissen P.
First page: e202108047
Abstract: Hepatocytes display a unique biaxial polarity with shared apical luminal connections between adjacent hepatocytes that merge into a network of bile canaliculi. Belicova et al. (2021. J. Cell Biol.https://doi.org/10.1083/jcb.202103003) discovered that hepatocyte apical membranes generate Rab35-dependent extensions that traverse the lumen and are essential for bile canalicular formation and maintenance.
PubDate: Mon, 13 Sep 2021 00:00:00 GMT
DOI: 10.1083/jcb.202108047
Issue No: Vol. 220, No. 10 (2021)
- Preventing aneuploidy: The groom must wait until the bride is ready
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Authors: Verlhac M.
First page: e202108030
Abstract: Fertilization often triggers the final step of haploidization of the female gamete genome. In this issue, Mori et al. (2021. J. Cell Biol.https://doi.org/10.1083/jcb.202012001) identify two successive actin-dependent mechanisms that delay fusion of maternal and paternal chromosomes, preventing inadvertent elimination of paternal chromosomes together with maternal ones.
PubDate: Fri, 10 Sep 2021 00:00:00 GMT
DOI: 10.1083/jcb.202108030
Issue No: Vol. 220, No. 10 (2021)
- GOLPH3 keeps the Golgi residents at home
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Authors: Lowe M.
First page: e202108147
Abstract: In this issue of JCB, Welch et al. (2021. J. Cell Biol.https://doi.org/10.1083/jcb.202106115) show that GOLPH3 mediates the sorting of numerous Golgi proteins into recycling COPI transport vesicles. This explains how many resident proteins are retained at the Golgi and reveals a key role for GOLPH3 in maintaining Golgi homeostasis.
PubDate: Fri, 03 Sep 2021 00:00:00 GMT
DOI: 10.1083/jcb.202108147
Issue No: Vol. 220, No. 10 (2021)
- GOLPH3 and GOLPH3L are broad-spectrum COPI adaptors for sorting into
intra-Golgi transport vesicles-
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Authors: Welch LG; Peak-Chew S, Begum F, et al.
First page: e202106115
Abstract: The fidelity of Golgi glycosylation is, in part, ensured by compartmentalization of enzymes within the stack. The COPI adaptor GOLPH3 has been shown to interact with the cytoplasmic tails of a subset of Golgi enzymes and direct their retention. However, other mechanisms of retention, and other roles for GOLPH3, have been proposed, and a comprehensive characterization of the clientele of GOLPH3 and its paralogue GOLPH3L is lacking. GOLPH3’s role is of particular interest as it is frequently amplified in several solid tumor types. Here, we apply two orthogonal proteomic methods to identify GOLPH3+3L clients and find that they act in diverse glycosylation pathways or have other roles in the Golgi. Binding studies, bioinformatics, and a Golgi retention assay show that GOLPH3+3L bind the cytoplasmic tails of their clients through membrane-proximal positively charged residues. Furthermore, deletion of GOLPH3+3L causes multiple defects in glycosylation. Thus, GOLPH3+3L are major COPI adaptors that impinge on most, if not all, of the glycosylation pathways of the Golgi.
PubDate: Thu, 02 Sep 2021 00:00:00 GMT
DOI: 10.1083/jcb.202106115
Issue No: Vol. 220, No. 10 (2021)
- The cell biology of fertilization: Gamete attachment and fusion
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Authors: Siu KK; Serrão VB, Ziyyat A, et al.
First page: e202102146
Abstract: Fertilization is defined as the union of two gametes. During fertilization, sperm and egg fuse to form a diploid zygote to initiate prenatal development. In mammals, fertilization involves multiple ordered steps, including the acrosome reaction, zona pellucida penetration, sperm–egg attachment, and membrane fusion. Given the success of in vitro fertilization, one would think that the mechanisms of fertilization are understood; however, the precise details for many of the steps in fertilization remain a mystery. Recent studies using genetic knockout mouse models and structural biology are providing valuable insight into the molecular basis of sperm–egg attachment and fusion. Here, we review the cell biology of fertilization, specifically summarizing data from recent structural and functional studies that provide insights into the interactions involved in human gamete attachment and fusion.
PubDate: Mon, 30 Aug 2021 00:00:00 GMT
DOI: 10.1083/jcb.202102146
Issue No: Vol. 220, No. 10 (2021)
- Depolarization induces nociceptor sensitization by Ca V 1.2-mediated
PKA-II activation-
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Authors: Isensee J; van Cann M, Despang P, et al.
First page: e202002083
Abstract: Depolarization drives neuronal plasticity. However, whether depolarization drives sensitization of peripheral nociceptive neurons remains elusive. By high-content screening (HCS) microscopy, we revealed that depolarization of cultured sensory neurons rapidly activates protein kinase A type II (PKA-II) in nociceptors by calcium influx through CaV1.2 channels. This effect was modulated by calpains but insensitive to inhibitors of cAMP formation, including opioids. In turn, PKA-II phosphorylated Ser1928 in the distal C terminus of CaV1.2, thereby increasing channel gating, whereas dephosphorylation of Ser1928 involved the phosphatase calcineurin. Patch-clamp and behavioral experiments confirmed that depolarization leads to calcium- and PKA-dependent sensitization of calcium currents ex vivo and local peripheral hyperalgesia in the skin in vivo. Our data suggest a local activity-driven feed-forward mechanism that selectively translates strong depolarization into further activity and thereby facilitates hypersensitivity of nociceptor terminals by a mechanism inaccessible to opioids.
PubDate: Wed, 25 Aug 2021 00:00:00 GMT
DOI: 10.1083/jcb.202002083
Issue No: Vol. 220, No. 10 (2021)
- Intracellular wetting mediates contacts between liquid compartments and
membrane-bound organelles-
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Authors: Kusumaatmaja H; May AI, Knorr RL.
First page: e202103175
Abstract: Protein-rich droplets, such as stress granules, P-bodies, and the nucleolus, perform diverse and specialized cellular functions. Recent evidence has shown the droplets, which are also known as biomolecular condensates or membrane-less compartments, form by phase separation. Many droplets also contact membrane-bound organelles, thereby functioning in development, intracellular degradation, and organization. These underappreciated interactions have major implications for our fundamental understanding of cells. Starting with a brief introduction to wetting phenomena, we summarize recent progress in the emerging field of droplet–membrane contact. We describe the physical mechanism of droplet–membrane interactions, discuss how these interactions remodel droplets and membranes, and introduce "membrane scaffolding" by liquids as a novel reshaping mechanism, thereby demonstrating that droplet–membrane interactions are elastic wetting phenomena. “Membrane-less” and “membrane-bound” condensates likely represent distinct wetting states that together link phase separation with mechanosensitivity and explain key structures observed during embryogenesis, during autophagy, and at synapses. We therefore contend that droplet wetting on membranes provides a robust and intricate means of intracellular organization.
PubDate: Tue, 24 Aug 2021 00:00:00 GMT
DOI: 10.1083/jcb.202103175
Issue No: Vol. 220, No. 10 (2021)
- Translational regulation in the brain by TDP-43 phase separation
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Authors: Gao J; Wang L, Ren X, et al.
First page: e202101019
Abstract: The in vivo physiological function of liquid–liquid phase separation (LLPS) that governs non–membrane-bound structures remains elusive. Among LLPS-prone proteins, TAR DNA-binding protein of 43 kD (TDP-43) is under intense investigation because of its close association with neurological disorders. Here, we generated mice expressing endogenous LLPS-deficient murine TDP-43. LLPS-deficient TDP-43 mice demonstrate impaired neuronal function and behavioral abnormalities specifically related to brain function. Brain neurons of these mice, however, did not show TDP-43 proteinopathy or neurodegeneration. Instead, the global rate of protein synthesis was found to be greatly enhanced by TDP-43 LLPS loss. Mechanistically, TDP-43 LLPS ablation increased its association with PABPC4, RPS6, RPL7, and other translational factors. The physical interactions between TDP-43 and translational factors relies on a motif, the deletion of which abolished the impact of LLPS-deficient TDP-43 on translation. Our findings show a specific physiological role for TDP-43 LLPS in the regulation of brain function and uncover an intriguing novel molecular mechanism of translational control by LLPS.
PubDate: Tue, 24 Aug 2021 00:00:00 GMT
DOI: 10.1083/jcb.202101019
Issue No: Vol. 220, No. 10 (2021)
- RanGTP and the actin cytoskeleton keep paternal and maternal chromosomes
apart during fertilization-
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Authors: Mori M; Yao T, Mishina T, et al.
First page: e202012001
Abstract: Zygotes require two accurate sets of parental chromosomes, one each from the mother and the father, to undergo normal embryogenesis. However, upon egg–sperm fusion in vertebrates, the zygote has three sets of chromosomes, one from the sperm and two from the egg. The zygote therefore eliminates one set of maternal chromosomes (but not the paternal chromosomes) into the polar body through meiosis, but how the paternal chromosomes are protected from maternal meiosis has been unclear. Here we report that RanGTP and F-actin dynamics prevent egg–sperm fusion in proximity to maternal chromosomes. RanGTP prevents the localization of Juno and CD9, egg membrane proteins that mediate sperm fusion, at the cell surface in proximity to maternal chromosomes. Following egg–sperm fusion, F-actin keeps paternal chromosomes away from maternal chromosomes. Disruption of these mechanisms causes the elimination of paternal chromosomes during maternal meiosis. This study reveals a novel critical mechanism that prevents aneuploidy in zygotes.
PubDate: Mon, 23 Aug 2021 00:00:00 GMT
DOI: 10.1083/jcb.202012001
Issue No: Vol. 220, No. 10 (2021)
- Pex30-like proteins function as adaptors at distinct ER membrane contact
sites-
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Authors: Ferreira J; Carvalho P.
First page: e202103176
Abstract: Membrane lipids and proteins synthesized in the ER are used for de novo assembly of organelles, such as lipid droplets and peroxisomes. After assembly, the growth of these organelles is supported by ER-derived lipids transferred at membrane contact sites (MCSs). How ER sites for organelle biogenesis and lipid transfer are established and regulated is unclear. Here, we investigate how the ER membrane protein Pex30 and its family members Pex28, Pex29, Pex31, and Pex32 target and function at multiple MCSs. We show that different Pex30 complexes function at distinct ER domains and MCSs. Pex30 targets ER–peroxisome MCSs when bound to Pex28 and Pex32, organizes the nuclear–vacuolar junction when bound to Pex29, and promotes the biogenesis of lipid droplets independently of other family members. Importantly, the reticulon homology domain (RHD) mediates the assembly of the various Pex30 complexes. Given the role of RHD in membrane shaping, our findings offer a mechanistic link between MCS and regulation of membrane curvature.
PubDate: Tue, 17 Aug 2021 00:00:00 GMT
DOI: 10.1083/jcb.202103176
Issue No: Vol. 220, No. 10 (2021)
- Membrane-bound SCF and VCAM-1 synergistically regulate the morphology of
hematopoietic stem cells-
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Authors: Hao J; Zhou H, Nemes K, et al.
First page: e202010118
Abstract: Membrane-bound factors expressed by niche stromal cells constitute a unique class of localized cues and regulate the long-term functions of adult stem cells, yet little is known about the underlying mechanisms. Here, we used a supported lipid bilayer (SLB) to recapitulate the membrane-bound interactions between hematopoietic stem cells (HSCs) and niche stromal cells. HSCs cluster membrane-bound stem cell factor (mSCF) at the HSC-SLB interface. They further form a polarized morphology with aggregated mSCF under a large protrusion through a synergy with VCAM-1 on the bilayer, which drastically enhances HSC adhesion. These features are unique to mSCF and HSCs among the factors and hematopoietic populations we examined. The mSCF–VCAM-1 synergy and the polarized HSC morphology require PI3K signaling and cytoskeletal reorganization. The synergy also enhances nuclear retention of FOXO3a, a crucial factor for HSC maintenance, and minimizes its loss induced by soluble SCF. Our work thus reveals a unique role and signaling mechanism of membrane-bound factors in regulating stem cell morphology and function.
PubDate: Tue, 17 Aug 2021 00:00:00 GMT
DOI: 10.1083/jcb.202010118
Issue No: Vol. 220, No. 10 (2021)
- Ultrastructural plasma membrane asymmetries in tension and curvature
promote yeast cell fusion-
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Authors: Muriel O; Michon L, Kukulski W, et al.
First page: e202103142
Abstract: Cell–cell fusion is central for sexual reproduction, and generally involves gametes of different shapes and sizes. In walled fission yeast Schizosaccharomyces pombe, the fusion of h+ and h− isogametes requires the fusion focus, an actin structure that concentrates glucanase-containing vesicles for cell wall digestion. Here, we present a quantitative correlative light and electron microscopy (CLEM) tomographic dataset of the fusion site, which reveals the fusion focus ultrastructure. Unexpectedly, gametes show marked asymmetries: a taut, convex plasma membrane of h− cells progressively protrudes into a more slack, wavy plasma membrane of h+ cells. Asymmetries are relaxed upon fusion, with observations of ramified fusion pores. h+ cells have a higher exo-/endocytosis ratio than h− cells, and local reduction in exocytosis strongly diminishes membrane waviness. Reciprocally, turgor pressure reduction specifically in h− cells impedes their protrusions into h+ cells and delays cell fusion. We hypothesize that asymmetric membrane conformations, due to differential turgor pressure and exocytosis/endocytosis ratios between mating types, favor cell–cell fusion.
PubDate: Thu, 12 Aug 2021 00:00:00 GMT
DOI: 10.1083/jcb.202103142
Issue No: Vol. 220, No. 10 (2021)
- Loss of centromeric RNA activates the spindle assembly checkpoint in
mammalian female meiosis I-
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Authors: Wu T; Lane SR, Morgan SL, et al.
First page: e202011153
Abstract: The repetitive sequences of DNA centromeric regions form the structural basis for kinetochore assembly. Recently they were found to be transcriptionally active in mitosis, with their RNAs providing noncoding functions. Here we explore the role, in mouse oocytes, of transcripts generated from within the minor satellite repeats. Depletion of minor satellite transcripts delayed progression through meiosis I by activation of the spindle assembly checkpoint. Arrested oocytes had poorly congressed chromosomes, and centromeres were frequently split by microtubules. Thus, we have demonstrated that the centromeric RNA plays a specific role in female meiosis I compared with mitosis and is required for maintaining the structural integrity of centromeres. This may contribute to the high aneuploidy rates observed in female meiosis.
PubDate: Wed, 11 Aug 2021 00:00:00 GMT
DOI: 10.1083/jcb.202011153
Issue No: Vol. 220, No. 10 (2021)
- FHL2 anchors mitochondria to actin and adapts mitochondrial dynamics to
glucose supply-
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Authors: Basu H; Pekkurnaz G, Falk J, et al.
First page: e201912077
Abstract: Mitochondrial movement and distribution are fundamental to their function. Here we report a mechanism that regulates mitochondrial movement by anchoring mitochondria to the F-actin cytoskeleton. This mechanism is activated by an increase in glucose influx and the consequent O-GlcNAcylation of TRAK (Milton), a component of the mitochondrial motor-adaptor complex. The protein four and a half LIM domains protein 2 (FHL2) serves as the anchor. FHL2 associates with O-GlcNAcylated TRAK and is both necessary and sufficient to drive the accumulation of F-actin around mitochondria and to arrest mitochondrial movement by anchoring to F-actin. Disruption of F-actin restores mitochondrial movement that had been arrested by either TRAK O-GlcNAcylation or forced direction of FHL2 to mitochondria. This pathway for mitochondrial immobilization is present in both neurons and non-neuronal cells and can thereby adapt mitochondrial dynamics to changes in glucose availability.
PubDate: Tue, 03 Aug 2021 00:00:00 GMT
DOI: 10.1083/jcb.201912077
Issue No: Vol. 220, No. 10 (2021)
- William R. Brinkley: A giant in biomedical research and public policy
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Authors: Gerbi SA; Palazzo RE, Earnshaw WC, et al.
First page: e202106102
PubDate: Tue, 03 Aug 2021 00:00:00 GMT
DOI: 10.1083/jcb.202106102
Issue No: Vol. 220, No. 10 (2021)
- Anisotropic expansion of hepatocyte lumina enforced by apical bulkheads
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Authors: Belicova L; Repnik U, Delpierre J, et al.
First page: e202103003
Abstract: Lumen morphogenesis results from the interplay between molecular pathways and mechanical forces. In several organs, epithelial cells share their apical surfaces to form a tubular lumen. In the liver, however, hepatocytes share the apical surface only between adjacent cells and form narrow lumina that grow anisotropically, generating a 3D network of bile canaliculi (BC). Here, by studying lumenogenesis in differentiating mouse hepatoblasts in vitro, we discovered that adjacent hepatocytes assemble a pattern of specific extensions of the apical membrane traversing the lumen and ensuring its anisotropic expansion. These previously unrecognized structures form a pattern, reminiscent of the bulkheads of boats, also present in the developing and adult liver. Silencing of Rab35 resulted in loss of apical bulkheads and lumen anisotropy, leading to cyst formation. Strikingly, we could reengineer hepatocyte polarity in embryonic liver tissue, converting BC into epithelial tubes. Our results suggest that apical bulkheads are cell-intrinsic anisotropic mechanical elements that determine the elongation of BC during liver tissue morphogenesis.
PubDate: Fri, 30 Jul 2021 00:00:00 GMT
DOI: 10.1083/jcb.202103003
Issue No: Vol. 220, No. 10 (2021)
- Lipid anchoring and electrostatic interactions target NOT-LIKE-DAD to
pollen endo-plasma membrane-
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Authors: Gilles LM; Calhau AM, La Padula V, et al.
First page: e202010077
Abstract: Phospholipases cleave phospholipids, major membrane constituents. They are thus essential for many developmental processes, including male gamete development. In flowering plants, mutation of phospholipase NOT-LIKE-DAD (NLD, also known as MTL or ZmPLA1) leads to peculiar defects in sexual reproduction, notably the induction of maternal haploid embryos. Contrary to previous reports, NLD does not localize to cytosol and plasma membrane of sperm cells but to the pollen endo-plasma membrane (endo-PM), a specific membrane derived from the PM of the pollen vegetative cell that encircles the two sperm cells. After pollen tube burst, NLD localizes at the apical region of the egg apparatus. Pharmacological approaches coupled with targeted mutagenesis revealed that lipid anchoring together with electrostatic interactions are involved in the attachment of NLD to this atypical endo-PM. Membrane surface-charge and lipid biosensors indicated that phosphatidylinositol-4,5-bisphosphate is enriched in the endo-PM, uncovering a unique example of how membrane electrostatic properties can define a specific polar domain (i.e., endo-PM), which is critical for plant reproduction and gamete formation.
PubDate: Thu, 29 Jul 2021 00:00:00 GMT
DOI: 10.1083/jcb.202010077
Issue No: Vol. 220, No. 10 (2021)
- XMAP215 promotes microtubule catastrophe by disrupting the growing
microtubule end-
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Authors: Farmer V; Arpağ G, Hall SL, et al.
First page: e202012144
Abstract: The GTP-tubulin cap is widely accepted to protect microtubules against catastrophe. The GTP-cap size is thought to increase with the microtubule growth rate, presumably endowing fast-growing microtubules with enhanced stability. It is unknown what GTP-cap properties permit frequent microtubule catastrophe despite fast growth. Here, we investigate microtubules growing in the presence and absence of the polymerase XMAP215. Using EB1 as a GTP-cap marker, we find that GTP-cap size increases regardless of whether growth acceleration is achieved by increasing tubulin concentration or by XMAP215. Despite increased mean GTP-cap size, microtubules grown with XMAP215 display increased catastrophe frequency, in contrast to microtubules grown with more tubulin, for which catastrophe is abolished. However, microtubules polymerized with XMAP215 have large fluctuations in growth rate; display tapered and curled ends; and undergo catastrophe at faster growth rates and with higher EB1 end-localization. Our results suggest that structural perturbations induced by XMAP215 override the protective effects of the GTP-cap, ultimately driving microtubule catastrophe.
PubDate: Thu, 29 Jul 2021 00:00:00 GMT
DOI: 10.1083/jcb.202012144
Issue No: Vol. 220, No. 10 (2021)
- Retinyl esters form lipid droplets independently of triacylglycerol and
seipin-
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Authors: Molenaar MR; Yadav KK, Toulmay A, et al.
First page: e202011071
Abstract: Lipid droplets store neutral lipids, primarily triacylglycerol and steryl esters. Seipin plays a role in lipid droplet biogenesis and is thought to determine the site of lipid droplet biogenesis and the size of newly formed lipid droplets. Here we show a seipin-independent pathway of lipid droplet biogenesis. In silico and in vitro experiments reveal that retinyl esters have the intrinsic propensity to sequester and nucleate in lipid bilayers. Production of retinyl esters in mammalian and yeast cells that do not normally produce retinyl esters causes the formation of lipid droplets, even in a yeast strain that produces only retinyl esters and no other neutral lipids. Seipin does not determine the size or biogenesis site of lipid droplets composed of only retinyl esters or steryl esters. These findings indicate that the role of seipin in lipid droplet biogenesis depends on the type of neutral lipid stored in forming droplets.
PubDate: Thu, 29 Jul 2021 00:00:00 GMT
DOI: 10.1083/jcb.202011071
Issue No: Vol. 220, No. 10 (2021)
- Signal strength controls the rate of polarization within CTLs during
killing-
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Authors: Frazer GL; Gawden-Bone CM, Dieckmann NG, et al.
First page: e202104093
Abstract: Cytotoxic T lymphocytes (CTLs) are key effector cells in the immune response against viruses and cancers, killing targets with high precision. Target cell recognition by CTL triggers rapid polarization of intracellular organelles toward the synapse formed with the target cell, delivering cytolytic granules to the immune synapse. Single amino acid changes within peptides binding MHC class I (pMHCs) are sufficient to modulate the degree of killing, but exactly how this impacts the choreography of centrosome polarization and granule delivery to the target cell remains poorly characterized. Here we use 4D imaging and find that the pathways orchestrating killing within CTL are conserved irrespective of the signal strength. However, the rate of initiation along these pathways varies with signal strength. We find that increased strength of signal leads to an increased proportion of CTLs with prolonged dwell times, initial Ca2+ fluxes, centrosome docking, and granule polarization. Hence, TCR signal strength modulates the rate but not organization of effector CTL responses.
PubDate: Thu, 22 Jul 2021 00:00:00 GMT
DOI: 10.1083/jcb.202104093
Issue No: Vol. 220, No. 10 (2021)
- Intracellular nanovesicles mediate α5β1 integrin trafficking
during cell migration-
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Authors: Larocque G; Moore DJ, Sittewelle M, et al.
First page: e202009028
Abstract: Membrane traffic is an important regulator of cell migration through the endocytosis and recycling of cell surface receptors such as integrin heterodimers. Intracellular nanovesicles (INVs) are transport vesicles that are involved in multiple membrane trafficking steps, including the recycling pathway. The only known marker for INVs is tumor protein D54 (TPD54/TPD52L2), a member of the TPD52-like protein family. Overexpression of TPD52-like family proteins in cancer has been linked to poor prognosis and an aggressive metastatic phenotype, which suggests cell migration may be altered under these conditions. Here, we show that TPD54 directly binds membrane and associates with INVs via a conserved positively charged motif in its C terminus. We describe how other TPD52-like proteins are also associated with INVs, and we document the Rab GTPase complement of all INVs. Depletion of TPD52-like proteins inhibits cell migration and invasion, while their overexpression boosts motility. We show that inhibition of migration is likely due to altered recycling of α5β1 integrins in INVs.
PubDate: Wed, 21 Jul 2021 00:00:00 GMT
DOI: 10.1083/jcb.202009028
Issue No: Vol. 220, No. 10 (2021)
- Specific KIF1A–adaptor interactions control selective cargo
recognition-
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Authors: Hummel JA; Hoogenraad CC.
First page: e202105011
Abstract: Intracellular transport in neurons is driven by molecular motors that carry many different cargos along cytoskeletal tracks in axons and dendrites. Identifying how motors interact with specific types of transport vesicles has been challenging. Here, we use engineered motors and cargo adaptors to systematically investigate the selectivity and regulation of kinesin-3 family member KIF1A–driven transport of dense core vesicles (DCVs), lysosomes, and synaptic vesicles (SVs). We dissect the role of KIF1A domains in motor activity and show that CC1 regulates autoinhibition, CC2 regulates motor dimerization, and CC3 and PH mediate cargo binding. Furthermore, we identify that phosphorylation of KIF1A is critical for binding to vesicles. Cargo specificity is achieved by specific KIF1A adaptors; MADD/Rab3GEP links KIF1A to SVs, and Arf-like GTPase Arl8A mediates interactions with DCVs and lysosomes. We propose a model where motor dimerization, posttranslational modifications, and specific adaptors regulate selective KIF1A cargo trafficking.
PubDate: Wed, 21 Jul 2021 00:00:00 GMT
DOI: 10.1083/jcb.202105011
Issue No: Vol. 220, No. 10 (2021)
- Coupled sterol synthesis and transport machineries at ER–endocytic
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Authors: Encinar del Dedo J; Fernández-Golbano I, Pastor L, et al.
First page: e202010016
Abstract: Sterols are unevenly distributed within cellular membranes. How their biosynthetic and transport machineries are organized to generate heterogeneity is largely unknown. We previously showed that the yeast sterol transporter Osh2 is recruited to endoplasmic reticulum (ER)–endocytic contacts to facilitate actin polymerization. We now find that a subset of sterol biosynthetic enzymes also localizes at these contacts and interacts with Osh2 and the endocytic machinery. Following the sterol dynamics, we show that Osh2 extracts sterols from these subdomains, which we name ERSESs (ER sterol exit sites). Further, we demonstrate that coupling of the sterol synthesis and transport machineries is required for endocytosis in mother cells, but not in daughters, where plasma membrane loading with accessible sterols and endocytosis are linked to secretion.
PubDate: Tue, 20 Jul 2021 00:00:00 GMT
DOI: 10.1083/jcb.202010016
Issue No: Vol. 220, No. 10 (2021)
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