RESUMO
An outbreak of over 1,000 COVID-19 cases in Provincetown, Massachusetts (MA), in July 2021-the first large outbreak mostly in vaccinated individuals in the US-prompted a comprehensive public health response, motivating changes to national masking recommendations and raising questions about infection and transmission among vaccinated individuals. To address these questions, we combined viral genomic and epidemiological data from 467 individuals, including 40% of outbreak-associated cases. The Delta variant accounted for 99% of cases in this dataset; it was introduced from at least 40 sources, but 83% of cases derived from a single source, likely through transmission across multiple settings over a short time rather than a single event. Genomic and epidemiological data supported multiple transmissions of Delta from and between fully vaccinated individuals. However, despite its magnitude, the outbreak had limited onward impact in MA and the US overall, likely due to high vaccination rates and a robust public health response.
Assuntos
COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/transmissão , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/virologia , Criança , Pré-Escolar , Busca de Comunicante/métodos , Surtos de Doenças , Feminino , Genoma Viral , Humanos , Lactente , Recém-Nascido , Masculino , Massachusetts/epidemiologia , Pessoa de Meia-Idade , Epidemiologia Molecular , Filogenia , SARS-CoV-2/classificação , Vacinação , Sequenciamento Completo do Genoma , Adulto JovemRESUMO
The function of biomolecular condensates is often restricted by condensate dissolution. Whether condensates can be suppressed without condensate dissolution is unclear. Here, we show that upstream regulators of the Hippo signaling pathway form functionally antagonizing condensates, and their coalescence into a common phase provides a mode of counteracting the function of biomolecular condensates without condensate dissolution. Specifically, the negative regulator SLMAP forms Hippo-inactivating condensates to facilitate pathway inhibition by the STRIPAK complex. In response to cell-cell contact or osmotic stress, the positive regulators AMOT and KIBRA form Hippo-activating condensates to facilitate pathway activation. The functionally antagonizing SLMAP and AMOT/KIBRA condensates further coalesce into a common phase to inhibit STRIPAK function. These findings provide a paradigm for restricting the activity of biomolecular condensates without condensate dissolution, shed light on the molecular principles of multiphase organization, and offer a conceptual framework for understanding upstream regulation of the Hippo signaling pathway.
Assuntos
Via de Sinalização Hippo , Proteínas Serina-Treonina Quinases , Transdução de SinaisRESUMO
Embryo morphogenesis is impacted by dynamic changes in tissue material properties, which have been proposed to occur via processes akin to phase transitions (PTs). Here, we show that rigidity percolation provides a simple and robust theoretical framework to predict material/structural PTs of embryonic tissues from local cell connectivity. By using percolation theory, combined with directly monitoring dynamic changes in tissue rheology and cell contact mechanics, we demonstrate that the zebrafish blastoderm undergoes a genuine rigidity PT, brought about by a small reduction in adhesion-dependent cell connectivity below a critical value. We quantitatively predict and experimentally verify hallmarks of PTs, including power-law exponents and associated discontinuities of macroscopic observables. Finally, we show that this uniform PT depends on blastoderm cells undergoing meta-synchronous divisions causing random and, consequently, uniform changes in cell connectivity. Collectively, our theoretical and experimental findings reveal the structural basis of material PTs in an organismal context.
Assuntos
Embrião não Mamífero/fisiologia , Desenvolvimento Embrionário , Animais , Blastoderma/citologia , Blastoderma/fisiologia , Caderinas/antagonistas & inibidores , Caderinas/genética , Caderinas/metabolismo , Adesão Celular , Embrião não Mamífero/citologia , Morfolinos/metabolismo , Reologia , Viscosidade , Peixe-Zebra/crescimento & desenvolvimentoRESUMO
Autophagy is a conserved catabolic homeostasis process central for cellular and organismal health. During autophagy, small single-membrane phagophores rapidly expand into large double-membrane autophagosomes to encapsulate diverse cargoes for degradation. It is thought that autophagic membranes are mainly derived from preformed organelle membranes. Instead, here we delineate a pathway that expands the phagophore membrane by localized phospholipid synthesis. Specifically, we find that the conserved acyl-CoA synthetase Faa1 accumulates on nucleated phagophores and locally activates fatty acids (FAs) required for phagophore elongation and autophagy. Strikingly, using isotopic FA tracing, we directly show that Faa1 channels activated FAs into the synthesis of phospholipids and promotes their assembly into autophagic membranes. Indeed, the first committed steps of de novo phospholipid synthesis at the ER, which forms stable contacts with nascent autophagosomes, are essential for autophagy. Together, our work illuminates how cells spatially tune synthesis and flux of phospholipids for autophagosome biogenesis during autophagy.
Assuntos
Autofagia/fisiologia , Ácidos Graxos/metabolismo , Fagossomos/metabolismo , Autofagossomos/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Membrana Celular/metabolismo , Coenzima A Ligases/metabolismo , Retículo Endoplasmático/metabolismo , Metabolismo dos Lipídeos , Proteínas de Membrana/metabolismo , Fagossomos/fisiologia , Fosfolipídeos/biossíntese , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
Long-distance RNA transport enables local protein synthesis at metabolically-active sites distant from the nucleus. This process ensures an appropriate spatial organization of proteins, vital to polarized cells such as neurons. Here, we present a mechanism for RNA transport in which RNA granules "hitchhike" on moving lysosomes. In vitro biophysical modeling, live-cell microscopy, and unbiased proximity labeling proteomics reveal that annexin A11 (ANXA11), an RNA granule-associated phosphoinositide-binding protein, acts as a molecular tether between RNA granules and lysosomes. ANXA11 possesses an N-terminal low complexity domain, facilitating its phase separation into membraneless RNA granules, and a C-terminal membrane binding domain, enabling interactions with lysosomes. RNA granule transport requires ANXA11, and amyotrophic lateral sclerosis (ALS)-associated mutations in ANXA11 impair RNA granule transport by disrupting their interactions with lysosomes. Thus, ANXA11 mediates neuronal RNA transport by tethering RNA granules to actively-transported lysosomes, performing a critical cellular function that is disrupted in ALS.
Assuntos
Anexinas/metabolismo , Transporte Axonal/fisiologia , Grânulos Citoplasmáticos/metabolismo , Lisossomos/metabolismo , RNA/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Animais , Animais Geneticamente Modificados , Anexinas/genética , Axônios/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Mutação , Ligação Proteica , Ratos/embriologia , Ratos Sprague-Dawley , Transfecção , Peixe-ZebraRESUMO
To maintain an asymmetric distribution of ions across membranes, protein pumps displace ions against their concentration gradient by using chemical energy. Here, we describe a functionally analogous but topologically opposite process that applies to the lipid transfer protein (LTP) oxysterol-binding protein (OSBP). This multidomain protein exchanges cholesterol for the phosphoinositide phosphatidylinositol 4-phosphate [PI(4)P] between two apposed membranes. Because of the subsequent hydrolysis of PI(4)P, this counterexchange is irreversible and contributes to the establishment of a cholesterol gradient along organelles of the secretory pathway. The facts that some natural anti-cancer molecules block OSBP and that many viruses hijack the OSBP cycle for the formation of intracellular replication organelles highlight the importance and potency of OSBP-mediated lipid exchange. The architecture of some LTPs is similar to that of OSBP, suggesting that the principles of the OSBP cycle-burning PI(4)P for the vectorial transfer of another lipid-might be general.
Assuntos
Colesterol/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Receptores de Esteroides/metabolismo , Transporte Biológico Ativo , Proteínas de Transporte/metabolismo , Complexo de Golgi/metabolismo , Humanos , Ligantes , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Modelos Biológicos , Modelos Moleculares , Oxisteróis/metabolismo , Domínios e Motivos de Interação entre Proteínas , Receptores de Esteroides/química , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Replicação Viral/fisiologiaRESUMO
Endoplasmic reticulum (ER) membrane contact sites (MCSs) mark positions where endosomes undergo fission for cargo sorting. To define the role of ER at this unique MCS, we targeted a promiscuous biotin ligase to cargo-sorting domains on endosome buds. This strategy identified the ER membrane protein TMCC1, a member of a conserved protein family. TMCC1 concentrates at the ER-endosome MCSs that are spatially and temporally linked to endosome fission. When TMCC1 is depleted, endosome morphology is normal, buds still form, but ER-associated bud fission and subsequent cargo sorting to the Golgi are impaired. We find that the endosome-localized actin regulator Coronin 1C is required for ER-associated fission of actin-dependent cargo-sorting domains. Coronin 1C is recruited to endosome buds independently of TMCC1, while TMCC1/ER recruitment requires Coronin 1C. This link between TMCC1 and Coronin 1C suggests that the timing of TMCC1-dependent ER recruitment is tightly regulated to occur after cargo has been properly sequestered into the bud.
Assuntos
Retículo Endoplasmático/metabolismo , Endossomos/metabolismo , Proteínas de Membrana/metabolismo , Animais , Células COS , Canais de Cálcio , Chlorocebus aethiops , Retículo Endoplasmático/fisiologia , Endossomos/fisiologia , Complexo de Golgi/metabolismo , Células HeLa , Humanos , Proteínas dos Microfilamentos/fisiologia , Microtúbulos/metabolismo , Transporte Proteico/fisiologiaRESUMO
The mechanisms underlying sterol transport in mammalian cells are poorly understood. In particular, how cholesterol internalized from HDL is made available to the cell for storage or modification is unknown. Here, we describe three ER-resident proteins (Aster-A, -B, -C) that bind cholesterol and facilitate its removal from the plasma membrane. The crystal structure of the central domain of Aster-A broadly resembles the sterol-binding fold of mammalian StARD proteins, but sequence differences in the Aster pocket result in a distinct mode of ligand binding. The Aster N-terminal GRAM domain binds phosphatidylserine and mediates Aster recruitment to plasma membrane-ER contact sites in response to cholesterol accumulation in the plasma membrane. Mice lacking Aster-B are deficient in adrenal cholesterol ester storage and steroidogenesis because of an inability to transport cholesterol from SR-BI to the ER. These findings identify a nonvesicular pathway for plasma membrane to ER sterol trafficking in mammals.
Assuntos
HDL-Colesterol/metabolismo , Proteínas de Membrana/fisiologia , Proteínas de Membrana/ultraestrutura , Células 3T3 , Animais , Transporte Biológico/fisiologia , Antígenos CD36/metabolismo , Células CHO , Proteínas de Transporte/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Membrana Celular/fisiologia , Colesterol/metabolismo , Cricetulus , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/fisiologia , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Membranas Mitocondriais/metabolismo , Alinhamento de Sequência , Esteróis/metabolismoRESUMO
Cell communication within tissues is mediated by multiple paracrine signals including growth factors, which control cell survival and proliferation. Cells and the growth factors they produce and receive constitute a circuit with specific properties that ensure homeostasis. Here, we used computational and experimental approaches to characterize the features of cell circuits based on growth factor exchange between macrophages and fibroblasts, two cell types found in most mammalian tissues. We found that the macrophage-fibroblast cell circuit is stable and robust to perturbations. Analytical screening of all possible two-cell circuit topologies revealed the circuit features sufficient for stability, including environmental constraint and negative-feedback regulation. Moreover, we found that cell-cell contact is essential for the stability of the macrophage-fibroblast circuit. These findings illustrate principles of cell circuit design and provide a quantitative perspective on cell interactions.
Assuntos
Comunicação Celular/fisiologia , Proliferação de Células/fisiologia , Fibroblastos/metabolismo , Macrófagos/metabolismo , Animais , Sobrevivência Celular/fisiologia , Feminino , Fibroblastos/citologia , Macrófagos/citologia , Masculino , Camundongos , Camundongos TransgênicosRESUMO
In eukaryotic cells, organelles and the cytoskeleton undergo highly dynamic yet organized interactions capable of orchestrating complex cellular functions. Visualizing these interactions requires noninvasive, long-duration imaging of the intracellular environment at high spatiotemporal resolution and low background. To achieve these normally opposing goals, we developed grazing incidence structured illumination microscopy (GI-SIM) that is capable of imaging dynamic events near the basal cell cortex at 97-nm resolution and 266 frames/s over thousands of time points. We employed multi-color GI-SIM to characterize the fast dynamic interactions of diverse organelles and the cytoskeleton, shedding new light on the complex behaviors of these structures. Precise measurements of microtubule growth or shrinkage events helped distinguish among models of microtubule dynamic instability. Analysis of endoplasmic reticulum (ER) interactions with other organelles or microtubules uncovered new ER remodeling mechanisms, such as hitchhiking of the ER on motile organelles. Finally, ER-mitochondria contact sites were found to promote both mitochondrial fission and fusion.
Assuntos
Retículo Endoplasmático/metabolismo , Microtúbulos/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Animais , Células COS , Linhagem Celular Tumoral , Chlorocebus aethiops , Humanos , Microscopia de FluorescênciaRESUMO
Phospholipids are synthesized primarily within the endoplasmic reticulum and are subsequently distributed to various subcellular membranes to maintain the unique lipid composition of specific organelles. As a result, in most cases, the steady-state localization of membrane phospholipids does not match their site of synthesis. This raises the question of how diverse lipid species reach their final membrane destinations and what molecular processes provide the energy to maintain the lipid gradients that exist between various membrane compartments. Recent studies have highlighted the role of inositol phospholipids in the nonvesicular transport of lipids at membrane contact sites. This review attempts to summarize our current understanding of these complex lipid dynamics and highlights their implications for defining future research directions.
Assuntos
Transporte Biológico , Retículo Endoplasmático/metabolismo , Metabolismo dos Lipídeos , Animais , Humanos , Lipídeos/biossíntese , Lipídeos/química , Organelas/química , Organelas/metabolismoRESUMO
Long interspersed element-1 (LINE-1 or L1) comprises 17% of the human genome, continuously generates genetic variations, and causes disease in certain cases. However, the regulation and function of L1 remain poorly understood. Here, we uncover that L1 can enrich RNA polymerase IIs (RNA Pol IIs), express L1 chimeric transcripts, and create contact domain boundaries in human cells. This impact of L1 is restricted by a nuclear matrix protein scaffold attachment factor B (SAFB) that recognizes transcriptionally active L1s by binding L1 transcripts to inhibit RNA Pol II enrichment. Acute inhibition of RNA Pol II transcription abolishes the domain boundaries associated with L1 chimeric transcripts, indicating a transcription-dependent mechanism. Deleting L1 impairs domain boundary formation, and L1 insertions during evolution have introduced species-specific domain boundaries. Our data show that L1 can create RNA Pol II-enriched regions that alter genome organization and that SAFB regulates L1 and RNA Pol II activity to preserve gene regulation.
Assuntos
Elementos Nucleotídeos Longos e Dispersos , Proteínas de Ligação à Região de Interação com a Matriz , RNA Polimerase II , Receptores de Estrogênio , Transcrição Gênica , Humanos , RNA Polimerase II/metabolismo , RNA Polimerase II/genética , Elementos Nucleotídeos Longos e Dispersos/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteínas Associadas à Matriz Nuclear/genética , Regulação da Expressão Gênica , Ligação Proteica , Células HEK293 , Genoma HumanoRESUMO
Metabolic enzymes can adapt during energy stress, but the consequences of these adaptations remain understudied. Here, we discovered that hexokinase 1 (HK1), a key glycolytic enzyme, forms rings around mitochondria during energy stress. These HK1-rings constrict mitochondria at contact sites with the endoplasmic reticulum (ER) and mitochondrial dynamics protein (MiD51). HK1-rings prevent mitochondrial fission by displacing the dynamin-related protein 1 (Drp1) from mitochondrial fission factor (Mff) and mitochondrial fission 1 protein (Fis1). The disassembly of HK1-rings during energy restoration correlated with mitochondrial fission. Mechanistically, we identified that the lack of ATP and glucose-6-phosphate (G6P) promotes the formation of HK1-rings. Mutations that affect the formation of HK1-rings showed that HK1-rings rewire cellular metabolism toward increased TCA cycle activity. Our findings highlight that HK1 is an energy stress sensor that regulates the shape, connectivity, and metabolic activity of mitochondria. Thus, the formation of HK1-rings may affect mitochondrial function in energy-stress-related pathologies.
Assuntos
Dinaminas , Metabolismo Energético , Hexoquinase , Mitocôndrias , Dinâmica Mitocondrial , Proteínas Mitocondriais , Hexoquinase/metabolismo , Hexoquinase/genética , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/genética , Mitocôndrias/enzimologia , Dinaminas/metabolismo , Dinaminas/genética , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Animais , Trifosfato de Adenosina/metabolismo , Estresse Fisiológico , Retículo Endoplasmático/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Ciclo do Ácido Cítrico , Glucose-6-Fosfato/metabolismo , Camundongos , Células HeLa , Células HEK293 , GTP Fosfo-Hidrolases/metabolismo , GTP Fosfo-Hidrolases/genética , MutaçãoRESUMO
Autophagy is a conserved intracellular degradation pathway that generates de novo double-membrane autophagosomes to target a wide range of material for lysosomal degradation. In multicellular organisms, autophagy initiation requires the timely assembly of a contact site between the ER and the nascent autophagosome. Here, we report the in vitro reconstitution of a full-length seven-subunit human autophagy initiation supercomplex built on a core complex of ATG13-101 and ATG9. Assembly of this core complex requires the rare ability of ATG13 and ATG101 to switch between distinct folds. The slow spontaneous metamorphic conversion is rate limiting for the self-assembly of the supercomplex. The interaction of the core complex with ATG2-WIPI4 enhances tethering of membrane vesicles and accelerates lipid transfer of ATG2 by both ATG9 and ATG13-101. Our work uncovers the molecular basis of the contact site and its assembly mechanisms imposed by the metamorphosis of ATG13-101 to regulate autophagosome biogenesis in space and time.
Assuntos
Autofagossomos , Autofagia , Humanos , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Autofagia/fisiologia , Autofagossomos/metabolismo , Proteínas de Membrana/metabolismo , LipídeosRESUMO
RNA-binding proteins (RBPs) bind at different positions of the pre-mRNA molecules to promote or reduce the usage of a particular exon. Seeking to understand the working principle of these positional effects, we develop a capture RIC-seq (CRIC-seq) method to enrich specific RBP-associated in situ proximal RNA-RNA fragments for deep sequencing. We determine hnRNPA1-, SRSF1-, and PTBP1-associated proximal RNA-RNA contacts and regulatory mechanisms in HeLa cells. Unexpectedly, the 3D RNA map analysis shows that PTBP1-associated loops in individual introns preferentially promote cassette exon splicing by accelerating asymmetric intron removal, whereas the loops spanning across cassette exon primarily repress splicing. These "positional rules" can faithfully predict PTBP1-regulated splicing outcomes. We further demonstrate that cancer-related splicing quantitative trait loci can disrupt RNA loops by reducing PTBP1 binding on pre-mRNAs to cause aberrant splicing in tumors. Our study presents a powerful method for exploring the functions of RBP-associated RNA-RNA proximal contacts in gene regulation and disease.
Assuntos
Proteína de Ligação a Regiões Ricas em Polipirimidinas , RNA , Humanos , RNA/metabolismo , Células HeLa , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Splicing de RNA/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Precursores de RNA/genética , Precursores de RNA/metabolismo , Processamento Alternativo , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Fatores de Processamento de Serina-Arginina/genéticaRESUMO
Tissue resident mast cells (MCs) rapidly initiate neutrophil infiltration upon inflammatory insult, yet the molecular mechanism is still unknown. Here, we demonstrated that MC-derived tumor necrosis factor (TNF) was crucial for neutrophil extravasation to sites of contact hypersensitivity-induced skin inflammation by promoting intraluminal crawling. MC-derived TNF directly primed circulating neutrophils via TNF receptor-1 (TNFR1) while being dispensable for endothelial cell activation. The MC-derived TNF was infused into the bloodstream by directional degranulation of perivascular MCs that were part of the vascular unit with access to the vessel lumen. Consistently, intravenous administration of MC granules boosted neutrophil extravasation. Pronounced and rapid intravascular MC degranulation was also observed upon IgE crosslinking or LPs challenge indicating a universal MC potential. Consequently, the directional MC degranulation of pro-inflammatory mediators into the bloodstream may represent an important target for therapeutic approaches aimed at dampening cytokine storm syndromes or shock symptoms, or intentionally pushing immune defense.
Assuntos
Vasos Sanguíneos/imunologia , Dermatite de Contato/imunologia , Inflamação/imunologia , Mastócitos/imunologia , Neutrófilos/imunologia , Pele/patologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Circulação Sanguínea , Degranulação Celular , Células Cultivadas , Doenças do Sistema Imunitário , Transtornos Leucocíticos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ativação de Neutrófilo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Vesículas Secretórias/metabolismo , Fator de Necrose Tumoral alfa/genéticaRESUMO
Lipids are unevenly distributed within and between cell membranes, thus defining organelle identity. Such distribution relies on local metabolic branches and mechanisms that move lipids. These processes are regulated by feedback mechanisms that decipher topographical information in organelle membranes and then regulate lipid levels or flows. In the endoplasmic reticulum, the major lipid source, transcriptional regulators and enzymes sense changes in membrane features to modulate lipid production. At the Golgi apparatus, lipid-synthesizing, lipid-flippase, and lipid-transport proteins (LTPs) collaborate to control lipid balance and distribution within the membrane to guarantee remodeling processes crucial for vesicular trafficking. Open questions exist regarding LTPs, which are thought to be lipid sensors that regulate lipid synthesis or carriers that transfer lipids between organelles across long distances or in contact sites. A novel model is that LTPs, by exchanging two different lipids, exploit one lipid gradient between two distinct membranes to build a second lipid gradient.
Assuntos
Membrana Celular/metabolismo , Lipídeos/química , Animais , Transporte Biológico , Retículo Endoplasmático/metabolismo , Retroalimentação Fisiológica , Fungos/fisiologia , Complexo de Golgi/metabolismo , Humanos , Membranas Intracelulares/metabolismo , Organelas/metabolismo , Fosfolipídeos/química , Transdução de Sinais , Esteróis/química , Rede trans-Golgi/químicaRESUMO
The regeneration of peripheral nerves is guided by regeneration tracks formed through an interplay of many cell types, but the underlying signaling pathways remain unclear. Here, we demonstrate that macrophages are mobilized ahead of Schwann cells in the nerve bridge after transection injury to participate in building regeneration tracks. This requires the function of guidance receptor Plexin-B2, which is robustly up-regulated in infiltrating macrophages in injured nerves. Conditional deletion of Plexin-B2 in myeloid lineage resulted in not only macrophage misalignment but also matrix disarray and Schwann cell disorganization, leading to misguided axons and delayed functional recovery. Plexin-B2 is not required for macrophage recruitment or activation but enables macrophages to steer clear of colliding axons, in particular the growth cones at the tip of regenerating axons, leading to parallel alignment postcollision. Together, our studies unveil a novel reparative function of macrophages and the importance of Plexin-B2-mediated collision-dependent contact avoidance between macrophages and regenerating axons in forming regeneration tracks during peripheral nerve regeneration.
Assuntos
Regeneração Nervosa , Nervos Periféricos , Axônios/fisiologia , Moléculas de Adesão Celular , Macrófagos/metabolismo , Regeneração Nervosa/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Nervos Periféricos/metabolismo , Células de Schwann/metabolismoRESUMO
Cholesterol metabolism is tightly associated with colorectal cancer (CRC). Nevertheless, the clinical benefit of statins, the inhibitor of cholesterol biogenesis mevalonate (MVA) pathway, is inconclusive, possibly because of a lack of patient stratification criteria. Here, we describe that YAP-mediated zinc finger MYND-type containing 8 (ZMYND8) expression sensitizes intestinal tumors to the inhibition of the MVA pathway. We show that the oncogenic activity of YAP relies largely on ZMYND8 to enhance intracellular de novo cholesterol biogenesis. Disruption of the ZMYND8-dependent MVA pathway greatly restricts the self-renewal capacity of Lgr5+ intestinal stem cells (ISCs) and intestinal tumorigenesis. Mechanistically, ZMYND8 and SREBP2 drive the enhancer-promoter interaction to facilitate the recruitment of Mediator complex, thus upregulating MVA pathway genes. Together, our results establish that the epigenetic reader ZMYND8 endows YAP-high intestinal cancer with metabolic vulnerability.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Colorretais/metabolismo , Ácido Mevalônico/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Camundongos , Camundongos Transgênicos , Proteínas Supressoras de Tumor/genética , Proteínas de Sinalização YAPRESUMO
Our cells are comprised of billions of proteins, lipids, and other small molecules packed into their respective subcellular organelles, with the daunting task of maintaining cellular homeostasis over a lifetime. However, it is becoming increasingly evident that organelles do not act as autonomous discrete units but rather as interconnected hubs that engage in extensive communication through membrane contacts. In the last few years, our understanding of how these contacts coordinate organelle function has redefined our view of the cell. This review aims to present novel findings on the cellular interorganelle communication network and how its dysfunction may contribute to aging and neurodegeneration. The consequences of disturbed interorganellar communication are intimately linked with age-related pathologies. Given that both aging and neurodegenerative diseases are characterized by the concomitant failure of multiple cellular pathways, coordination of organelle communication and function could represent an emerging regulatory mechanism critical for long-term cellular homeostasis. We anticipate that defining the relationships between interorganelle communication, aging, and neurodegeneration will open new avenues for therapeutics.