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1.
Annu Rev Immunol ; 39: 719-757, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33646859

RESUMO

The enigmatic eosinophil has emerged as an exciting component of the immune system, involved in a plethora of homeostatic and inflammatory responses. Substantial progress has been achieved through experimental systems manipulating eosinophils in vivo, initially in mice and more recently in humans. Researchers using eosinophil knockout mice have identified a contributory role for eosinophils in basal and inflammatory processes and protective immunity. Primarily fueled by the purported proinflammatory role of eosinophils in eosinophil-associated diseases, a series of anti-eosinophil therapeutics have emerged as a new class of drugs. These agents, which dramatically deplete eosinophils, provide a valuable opportunity to characterize the consequences of eosinophil knockout humans. Herein, we comparatively describe mouse and human eosinophil knockouts. We put forth the view that human eosinophils negatively contribute to a variety of diseases and, unlike mouse eosinophils, do not yet have an identified role in physiological health; thus, clarifying all roles of eosinophils remains an ongoing pursuit.


Assuntos
Eosinófilos , Preparações Farmacêuticas , Animais , Terapia Biológica , Humanos , Camundongos , Camundongos Knockout
2.
Annu Rev Immunol ; 37: 47-72, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30379593

RESUMO

Tuft cells-rare solitary chemosensory cells in mucosal epithelia-are undergoing intense scientific scrutiny fueled by recent discovery of unsuspected connections to type 2 immunity. These cells constitute a conduit by which ligands from the external space are sensed via taste-like signaling pathways to generate outputs unique among epithelial cells: the cytokine IL-25, eicosanoids associated with allergic immunity, and the neurotransmitter acetylcholine. The classic type II taste cell transcription factor POU2F3 is lineage defining, suggesting a conceptualization of these cells as widely distributed environmental sensors with effector functions interfacing type 2 immunity and neural circuits. Increasingly refined single-cell analytics have revealed diversity among tuft cells that extends from nasal epithelia and type II taste cells to ex-Aire-expressing medullary thymic cells and small-intestine cells that mediate tissue remodeling in response to colonizing helminths and protists.


Assuntos
Epitélio/fisiologia , Helmintíase/imunologia , Helmintos/fisiologia , Fatores de Transcrição de Octâmero/metabolismo , Células Receptoras Sensoriais/fisiologia , Células Th2/imunologia , Animais , Humanos , Sistema Imunitário , Interleucina-17/metabolismo , Sistema Nervoso , Neuroimunomodulação , Fatores de Transcrição de Octâmero/genética , Transdução de Sinais , Canais de Cátion TRPM/metabolismo
3.
Annu Rev Biochem ; 93(1): 317-338, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39094034

RESUMO

Discovered in 1993, inositol pyrophosphates are evolutionarily conserved signaling metabolites whose versatile modes of action are being increasingly appreciated. These include their emerging roles as energy regulators, phosphodonors, steric/allosteric regulators, and G protein-coupled receptor messengers. Through studying enzymes that metabolize inositol pyrophosphates, progress has also been made in elucidating the various cellular and physiological functions of these pyrophosphate-containing, energetic molecules. The two main forms of inositol pyrophosphates, 5-IP7 and IP8, synthesized respectively by inositol-hexakisphosphate kinases (IP6Ks) and diphosphoinositol pentakisphosphate kinases (PPIP5Ks), regulate phosphate homeostasis, ATP synthesis, and several other metabolic processes ranging from insulin secretion to cellular energy utilization. Here, we review the current understanding of the catalytic and regulatory mechanisms of IP6Ks and PPIP5Ks, as well as their counteracting phosphatases. We also highlight the genetic and cellular evidence implicating inositol pyrophosphates as essential mediators of mammalian metabolic homeostasis.


Assuntos
Fosfatos de Inositol , Fosfotransferases (Aceptor do Grupo Fosfato) , Transdução de Sinais , Humanos , Fosfatos de Inositol/metabolismo , Animais , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Homeostase , Metabolismo Energético , Trifosfato de Adenosina/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Monoéster Fosfórico Hidrolases/genética
4.
Cell ; 187(18): 4964-4980.e21, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39059380

RESUMO

The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.


Assuntos
Anticorpos Monoclonais , Anticorpos Antiprotozoários , Antígenos de Protozoários , Imunoglobulina G , Vacinas Antimaláricas , Malária Falciparum , Plasmodium falciparum , Proteínas de Protozoários , Animais , Humanos , Camundongos , Anticorpos Monoclonais/imunologia , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Proteínas de Transporte/imunologia , Epitopos/imunologia , Eritrócitos/parasitologia , Eritrócitos/imunologia , Imunoglobulina G/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Malária Falciparum/parasitologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia
5.
Cell ; 187(18): 4981-4995.e14, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39059381

RESUMO

Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is the most advanced blood-stage malaria vaccine candidate and is being evaluated for efficacy in endemic regions, emphasizing the need to study the underlying antibody response to RH5 during natural infection, which could augment or counteract responses to vaccination. Here, we found that RH5-reactive B cells were rare, and circulating immunoglobulin G (IgG) responses to RH5 were short-lived in malaria-exposed Malian individuals, despite repeated infections over multiple years. RH5-specific monoclonal antibodies isolated from eight malaria-exposed individuals mostly targeted non-neutralizing epitopes, in contrast to antibodies isolated from five RH5-vaccinated, malaria-naive UK individuals. However, MAD8-151 and MAD8-502, isolated from two malaria-exposed Malian individuals, were among the most potent neutralizers out of 186 antibodies from both cohorts and targeted the same epitopes as the most potent vaccine-induced antibodies. These results suggest that natural malaria infection may boost RH5-vaccine-induced responses and provide a clear strategy for the development of next-generation RH5 vaccines.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antiprotozoários , Antígenos de Protozoários , Vacinas Antimaláricas , Malária Falciparum , Plasmodium falciparum , Humanos , Anticorpos Neutralizantes/imunologia , Plasmodium falciparum/imunologia , Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Malária Falciparum/parasitologia , Vacinas Antimaláricas/imunologia , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Proteínas de Protozoários/imunologia , Anticorpos Monoclonais/imunologia , Adulto , Linfócitos B/imunologia , Epitopos/imunologia , Feminino , Mali , Proteínas de Transporte/imunologia , Masculino , Adolescente
6.
Cell ; 187(3): 585-595.e6, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38194968

RESUMO

Evolution of SARS-CoV-2 requires the reassessment of current vaccine measures. Here, we characterized BA.2.86 and XBB-derived variant FLip by investigating their neutralization alongside D614G, BA.1, BA.2, BA.4/5, XBB.1.5, and EG.5.1 by sera from 3-dose-vaccinated and bivalent-vaccinated healthcare workers, XBB.1.5-wave-infected first responders, and monoclonal antibody (mAb) S309. We assessed the biology of the variant spikes by measuring viral infectivity and membrane fusogenicity. BA.2.86 is less immune evasive compared to FLip and other XBB variants, consistent with antigenic distances. Importantly, distinct from XBB variants, mAb S309 was unable to neutralize BA.2.86, likely due to a D339H mutation based on modeling. BA.2.86 had relatively high fusogenicity and infectivity in CaLu-3 cells but low fusion and infectivity in 293T-ACE2 cells compared to some XBB variants, suggesting a potentially different conformational stability of BA.2.86 spike. Overall, our study underscores the importance of SARS-CoV-2 variant surveillance and the need for updated COVID-19 vaccines.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Evasão da Resposta Imune , SARS-CoV-2 , Humanos , Anticorpos Monoclonais , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/imunologia , SARS-CoV-2/classificação , SARS-CoV-2/fisiologia
7.
Cell ; 187(9): 2250-2268.e31, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38554706

RESUMO

Ubiquitin-dependent unfolding of the CMG helicase by VCP/p97 is required to terminate DNA replication. Other replisome components are not processed in the same fashion, suggesting that additional mechanisms underlie replication protein turnover. Here, we identify replisome factor interactions with a protein complex composed of AAA+ ATPases SPATA5-SPATA5L1 together with heterodimeric partners C1orf109-CINP (55LCC). An integrative structural biology approach revealed a molecular architecture of SPATA5-SPATA5L1 N-terminal domains interacting with C1orf109-CINP to form a funnel-like structure above a cylindrically shaped ATPase motor. Deficiency in the 55LCC complex elicited ubiquitin-independent proteotoxicity, replication stress, and severe chromosome instability. 55LCC showed ATPase activity that was specifically enhanced by replication fork DNA and was coupled to cysteine protease-dependent cleavage of replisome substrates in response to replication fork damage. These findings define 55LCC-mediated proteostasis as critical for replication fork progression and genome stability and provide a rationale for pathogenic variants seen in associated human neurodevelopmental disorders.


Assuntos
Adenosina Trifosfatases , Replicação do DNA , Instabilidade Genômica , Proteostase , Humanos , Adenosina Trifosfatases/metabolismo , Proteína com Valosina/metabolismo , Proteína com Valosina/genética , Células HEK293 , Proteínas de Ciclo Celular/metabolismo , ATPases Associadas a Diversas Atividades Celulares/metabolismo , ATPases Associadas a Diversas Atividades Celulares/genética
8.
Cell ; 187(15): 4010-4029.e16, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38917790

RESUMO

Mammalian blastocyst formation involves the specification of the trophectoderm followed by the differentiation of the inner cell mass into embryonic epiblast and extra-embryonic primitive endoderm (PrE). During this time, the embryo maintains a window of plasticity and can redirect its cellular fate when challenged experimentally. In this context, we found that the PrE alone was sufficient to regenerate a complete blastocyst and continue post-implantation development. We identify an in vitro population similar to the early PrE in vivo that exhibits the same embryonic and extra-embryonic potency and can form complete stem cell-based embryo models, termed blastoids. Commitment in the PrE is suppressed by JAK/STAT signaling, collaborating with OCT4 and the sustained expression of a subset of pluripotency-related transcription factors that safeguard an enhancer landscape permissive for multi-lineage differentiation. Our observations support the notion that transcription factor persistence underlies plasticity in regulative development and highlight the importance of the PrE in perturbed development.


Assuntos
Blastocisto , Diferenciação Celular , Endoderma , Animais , Endoderma/metabolismo , Endoderma/citologia , Camundongos , Blastocisto/metabolismo , Blastocisto/citologia , Linhagem da Célula , Fator 3 de Transcrição de Octâmero/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Transdução de Sinais , Desenvolvimento Embrionário , Janus Quinases/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição/metabolismo , Feminino , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/citologia
9.
Cell ; 2024 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-39426376

RESUMO

Synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are triggered by α-synuclein aggregation, triggering progressive neurodegeneration. However, the intracellular α-synuclein aggregation mechanism remains unclear. Herein, we demonstrate that RNA G-quadruplex assembly forms scaffolds for α-synuclein aggregation, contributing to neurodegeneration. Purified α-synuclein binds RNA G-quadruplexes directly through the N terminus. RNA G-quadruplexes undergo Ca2+-induced phase separation and assembly, accelerating α-synuclein sol-gel phase transition. In α-synuclein preformed fibril-treated neurons, RNA G-quadruplex assembly comprising synaptic mRNAs co-aggregates with α-synuclein upon excess cytoplasmic Ca2+ influx, eliciting synaptic dysfunction. Forced RNA G-quadruplex assembly using an optogenetic approach evokes α-synuclein aggregation, causing neuronal dysfunction and neurodegeneration. The administration of 5-aminolevulinic acid, a protoporphyrin IX prodrug, prevents RNA G-quadruplex phase separation, thereby attenuating α-synuclein aggregation, neurodegeneration, and progressive motor deficits in α-synuclein preformed fibril-injected synucleinopathic mice. Therefore, Ca2+ influx-induced RNA G-quadruplex assembly accelerates α-synuclein phase transition and aggregation, potentially contributing to synucleinopathies.

10.
Cell ; 187(21): 6088-6103.e18, 2024 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-39214079

RESUMO

5-Methylcytosine (5mC) is an established epigenetic mark in vertebrate genomic DNA, but whether its oxidation intermediates formed during TET-mediated DNA demethylation possess an instructive role of their own that is also physiologically relevant remains unresolved. Here, we reveal a 5-formylcytosine (5fC) nuclear chromocenter, which transiently forms during zygotic genome activation (ZGA) in Xenopus and mouse embryos. We identify this chromocenter as the perinucleolar compartment, a structure associated with RNA Pol III transcription. In Xenopus embryos, 5fC is highly enriched on Pol III target genes activated at ZGA, notably at oocyte-type tandem arrayed tRNA genes. By manipulating Tet and Tdg enzymes, we show that 5fC is required as a regulatory mark to promote Pol III recruitment as well as tRNA expression. Concordantly, 5fC modification of a tRNA transgene enhances its expression in vivo. The results establish 5fC as an activating epigenetic mark during zygotic reprogramming of Pol III gene expression.


Assuntos
Citosina , Epigênese Genética , RNA Polimerase III , Zigoto , Animais , Citosina/metabolismo , Citosina/análogos & derivados , Camundongos , Zigoto/metabolismo , RNA Polimerase III/metabolismo , RNA Polimerase III/genética , RNA de Transferência/metabolismo , RNA de Transferência/genética , Xenopus laevis/metabolismo , Xenopus laevis/embriologia , Xenopus laevis/genética , Xenopus/metabolismo , Xenopus/embriologia , Xenopus/genética , Feminino , Reprogramação Celular , Regulação da Expressão Gênica no Desenvolvimento , Oócitos/metabolismo
11.
Cell ; 187(12): 3039-3055.e14, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38848677

RESUMO

In the prevailing model, Lgr5+ cells are the only intestinal stem cells (ISCs) that sustain homeostatic epithelial regeneration by upward migration of progeny through elusive upper crypt transit-amplifying (TA) intermediates. Here, we identify a proliferative upper crypt population marked by Fgfbp1, in the location of putative TA cells, that is transcriptionally distinct from Lgr5+ cells. Using a kinetic reporter for time-resolved fate mapping and Fgfbp1-CreERT2 lineage tracing, we establish that Fgfbp1+ cells are multi-potent and give rise to Lgr5+ cells, consistent with their ISC function. Fgfbp1+ cells also sustain epithelial regeneration following Lgr5+ cell depletion. We demonstrate that FGFBP1, produced by the upper crypt cells, is an essential factor for crypt proliferation and epithelial homeostasis. Our findings support a model in which tissue regeneration originates from upper crypt Fgfbp1+ cells that generate progeny propagating bi-directionally along the crypt-villus axis and serve as a source of Lgr5+ cells in the crypt base.


Assuntos
Mucosa Intestinal , Receptores Acoplados a Proteínas G , Receptores Acoplados a Proteínas G/metabolismo , Animais , Camundongos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/citologia , Células-Tronco/metabolismo , Células-Tronco/citologia , Linhagem da Célula , Regeneração , Proliferação de Células , Células Epiteliais/metabolismo , Células Epiteliais/citologia , Camundongos Endogâmicos C57BL , Homeostase
12.
Cell ; 187(15): 4061-4077.e17, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38878777

RESUMO

NLRs constitute a large, highly conserved family of cytosolic pattern recognition receptors that are central to health and disease, making them key therapeutic targets. NLRC5 is an enigmatic NLR with mutations associated with inflammatory and infectious diseases, but little is known about its function as an innate immune sensor and cell death regulator. Therefore, we screened for NLRC5's role in response to infections, PAMPs, DAMPs, and cytokines. We identified that NLRC5 acts as an innate immune sensor to drive inflammatory cell death, PANoptosis, in response to specific ligands, including PAMP/heme and heme/cytokine combinations. NLRC5 interacted with NLRP12 and PANoptosome components to form a cell death complex, suggesting an NLR network forms similar to those in plants. Mechanistically, TLR signaling and NAD+ levels regulated NLRC5 expression and ROS production to control cell death. Furthermore, NLRC5-deficient mice were protected in hemolytic and inflammatory models, suggesting that NLRC5 could be a potential therapeutic target.


Assuntos
Inflamação , Peptídeos e Proteínas de Sinalização Intracelular , NAD , Animais , Camundongos , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , NAD/metabolismo , Humanos , Imunidade Inata , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Camundongos Knockout , Transdução de Sinais , Células HEK293 , Inflamassomos/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Receptores Toll-Like/metabolismo , Masculino , Citocinas/metabolismo , Proteínas de Ligação ao Cálcio
13.
Annu Rev Biochem ; 92: 333-349, 2023 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-37018846

RESUMO

Radical S-adenosylmethionine (SAM) enzymes use a site-differentiated [4Fe-4S] cluster and SAM to initiate radical reactions through liberation of the 5'-deoxyadenosyl (5'-dAdo•) radical. They form the largest enzyme superfamily, with more than 700,000 unique sequences currently, and their numbers continue to grow as a result of ongoing bioinformatics efforts. The range of extremely diverse, highly regio- and stereo-specific reactions known to be catalyzed by radical SAM superfamily members is remarkable. The common mechanism of radical initiation in the radical SAM superfamily is the focus of this review. Most surprising is the presence of an organometallic intermediate, Ω, exhibiting an Fe-C5'-adenosyl bond. Regioselective reductive cleavage of the SAM S-C5' bond produces 5'-dAdo• to form Ω, with the regioselectivity originating in the Jahn-Teller effect. Ω liberates the free 5'-dAdo• as the catalytically active intermediate through homolysis of the Fe-C5' bond, in analogy to Co-C5' bond homolysis in B12, which was once viewed as biology's choice of radical generator.


Assuntos
Proteínas Ferro-Enxofre , S-Adenosilmetionina , S-Adenosilmetionina/química , Proteínas Ferro-Enxofre/genética , Proteínas Ferro-Enxofre/química
14.
Cell ; 186(13): 2802-2822.e22, 2023 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-37220746

RESUMO

Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal antibody treatment, indicating a critical niche for C5 in antifungal immunity. We identified transcription of complement system genes as the top biological pathway induced in candidemic patients and as predictive of candidemia. Mechanistically, C5a-C5aR1 promoted fungal clearance and host survival in a mouse model of systemic candidiasis by stimulating phagocyte effector function and ERK- and AKT-dependent survival in infected tissues. C5ar1 ablation rewired macrophage metabolism downstream of mTOR, promoting their apoptosis and enhancing mortality through kidney injury. Besides hepatocyte-derived C5, local C5 produced intrinsically by phagocytes provided a key substrate for antifungal protection. Lower serum C5a concentrations or a C5 polymorphism that decreases leukocyte C5 expression correlated independently with poor patient outcomes. Thus, local, phagocyte-derived C5 production licenses phagocyte antimicrobial function and confers innate protection during systemic fungal infection.


Assuntos
Antifúngicos , Candidíase , Animais , Camundongos , Complemento C5/metabolismo , Fagócitos/metabolismo
15.
Cell ; 186(9): 1950-1967.e25, 2023 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-36996814

RESUMO

Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), lead to autism, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different developmental stages. We found that the forebrain undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes, but what are the consequences of perturbing this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of LNAAs and lipids are interconnected in the cortex. Deletion of Slc7a5 in neurons affects the postnatal metabolic state, leading to a shift in lipid metabolism. Additionally, it causes stage- and cell-type-specific alterations in neuronal activity patterns, resulting in a long-term circuit dysfunction.


Assuntos
Aminoácidos Neutros , Transportador 1 de Aminoácidos Neutros Grandes , Feminino , Humanos , Gravidez , Aminoácidos Neutros/genética , Aminoácidos Neutros/metabolismo , Encéfalo/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes/genética , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Mutação , Neurônios/metabolismo , Animais , Camundongos
16.
Cell ; 186(6): 1115-1126.e8, 2023 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-36931242

RESUMO

Previously, two men were cured of HIV-1 through CCR5Δ32 homozygous (CCR5Δ32/Δ32) allogeneic adult stem cell transplant. We report the first remission and possible HIV-1 cure in a mixed-race woman who received a CCR5Δ32/Δ32 haplo-cord transplant (cord blood cells combined with haploidentical stem cells from an adult) to treat acute myeloid leukemia (AML). Peripheral blood chimerism was 100% CCR5Δ32/Δ32 cord blood by week 14 post-transplant and persisted through 4.8 years of follow-up. Immune reconstitution was associated with (1) loss of detectable replication-competent HIV-1 reservoirs, (2) loss of HIV-1-specific immune responses, (3) in vitro resistance to X4 and R5 laboratory variants, including pre-transplant autologous latent reservoir isolates, and (4) 18 months of HIV-1 control with aviremia, off antiretroviral therapy, starting at 37 months post-transplant. CCR5Δ32/Δ32 haplo-cord transplant achieved remission and a possible HIV-1 cure for a person of diverse ancestry, living with HIV-1, who required a stem cell transplant for acute leukemia.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Infecções por HIV , HIV-1 , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Masculino , Adulto , Feminino , Humanos , Sangue Fetal , Leucemia Mieloide Aguda/terapia
17.
Cell ; 186(4): 748-763.e15, 2023 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-36758548

RESUMO

Although many prokaryotes have glycolysis alternatives, it's considered as the only energy-generating glucose catabolic pathway in eukaryotes. Here, we managed to create a hybrid-glycolysis yeast. Subsequently, we identified an inositol pyrophosphatase encoded by OCA5 that could regulate glycolysis and respiration by adjusting 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP7) levels. 5-InsP7 levels could regulate the expression of genes involved in glycolysis and respiration, representing a global mechanism that could sense ATP levels and regulate central carbon metabolism. The hybrid-glycolysis yeast did not produce ethanol during growth under excess glucose and could produce 2.68 g/L free fatty acids, which is the highest reported production in shake flask of Saccharomyces cerevisiae. This study demonstrated the significance of hybrid-glycolysis yeast and determined Oca5 as an inositol pyrophosphatase controlling the balance between glycolysis and respiration, which may shed light on the role of inositol pyrophosphates in regulating eukaryotic metabolism.


Assuntos
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Difosfatos/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Fosfatos de Inositol/genética , Fosfatos de Inositol/metabolismo , Glicólise/genética , Respiração , Pirofosfatases/metabolismo , Glucose/metabolismo
18.
Cell ; 186(16): 3460-3475.e23, 2023 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-37478862

RESUMO

All eukaryotes require intricate protein networks to translate developmental signals into accurate cell fate decisions. Mutations that disturb interactions between network components often result in disease, but how the composition and dynamics of complex networks are established remains poorly understood. Here, we identify the E3 ligase UBR5 as a signaling hub that helps degrade unpaired subunits of multiple transcriptional regulators that act within a network centered on the c-Myc oncoprotein. Biochemical and structural analyses show that UBR5 binds motifs that only become available upon complex dissociation. By rapidly turning over unpaired transcription factor subunits, UBR5 establishes dynamic interactions between transcriptional regulators that allow cells to effectively execute gene expression while remaining receptive to environmental signals. We conclude that orphan quality control plays an essential role in establishing dynamic protein networks, which may explain the conserved need for protein degradation during transcription and offers opportunities to modulate gene expression in disease.


Assuntos
Fatores de Transcrição , Ubiquitina-Proteína Ligases , Humanos , Expressão Gênica , Células HEK293 , Células HeLa , Mutação , Transdução de Sinais , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
19.
Cell ; 186(13): 2897-2910.e19, 2023 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-37295417

RESUMO

Sperm motility is crucial for successful fertilization. Highly decorated doublet microtubules (DMTs) form the sperm tail skeleton, which propels the movement of spermatozoa. Using cryo-electron microscopy (cryo-EM) and artificial intelligence (AI)-based modeling, we determined the structures of mouse and human sperm DMTs and built an atomic model of the 48-nm repeat of the mouse sperm DMT. Our analysis revealed 47 DMT-associated proteins, including 45 microtubule inner proteins (MIPs). We identified 10 sperm-specific MIPs, including seven classes of Tektin5 in the lumen of the A tubule and FAM166 family members that bind the intra-tubulin interfaces. Interestingly, the human sperm DMT lacks some MIPs compared with the mouse sperm DMT. We also discovered variants in 10 distinct MIPs associated with a subtype of asthenozoospermia characterized by impaired sperm motility without evident morphological abnormalities. Our study highlights the conservation and tissue/species specificity of DMTs and expands the genetic spectrum of male infertility.


Assuntos
Inteligência Artificial , Infertilidade Masculina , Masculino , Humanos , Microscopia Crioeletrônica , Motilidade dos Espermatozoides/genética , Sêmen , Espermatozoides , Microtúbulos/metabolismo , Cauda do Espermatozoide/química , Cauda do Espermatozoide/metabolismo , Proteínas dos Microtúbulos/química , Infertilidade Masculina/genética , Infertilidade Masculina/metabolismo
20.
Cell ; 186(9): 1930-1949.e31, 2023 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-37071993

RESUMO

Cortical circuits are composed predominantly of pyramidal-to-pyramidal neuron connections, yet their assembly during embryonic development is not well understood. We show that mouse embryonic Rbp4-Cre cortical neurons, transcriptomically closest to layer 5 pyramidal neurons, display two phases of circuit assembly in vivo. At E14.5, they form a multi-layered circuit motif, composed of only embryonic near-projecting-type neurons. By E17.5, this transitions to a second motif involving all three embryonic types, analogous to the three adult layer 5 types. In vivo patch clamp recordings and two-photon calcium imaging of embryonic Rbp4-Cre neurons reveal active somas and neurites, tetrodotoxin-sensitive voltage-gated conductances, and functional glutamatergic synapses, from E14.5 onwards. Embryonic Rbp4-Cre neurons strongly express autism-associated genes and perturbing these genes interferes with the switch between the two motifs. Hence, pyramidal neurons form active, transient, multi-layered pyramidal-to-pyramidal circuits at the inception of neocortex, and studying these circuits could yield insights into the etiology of autism.


Assuntos
Transtorno Autístico , Neocórtex , Células Piramidais , Animais , Feminino , Camundongos , Gravidez , Transtorno Autístico/genética , Transtorno Autístico/patologia , Mutação , Neocórtex/fisiologia , Neurônios/fisiologia , Células Piramidais/fisiologia
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