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1.
Immunity ; 51(5): 840-855.e5, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31606264

RESUMO

TCF-1 is a key transcription factor in progenitor exhausted CD8 T cells (Tex). Moreover, this Tex cell subset mediates responses to PD-1 checkpoint pathway blockade. However, the role of the transcription factor TCF-1 in early fate decisions and initial generation of Tex cells is unclear. Single-cell RNA sequencing (scRNA-seq) and lineage tracing identified a TCF-1+Ly108+PD-1+ CD8 T cell population that seeds development of mature Tex cells early during chronic infection. TCF-1 mediated the bifurcation between divergent fates, repressing development of terminal KLRG1Hi effectors while fostering KLRG1Lo Tex precursor cells, and PD-1 stabilized this TCF-1+ Tex precursor cell pool. TCF-1 mediated a T-bet-to-Eomes transcription factor transition in Tex precursors by promoting Eomes expression and drove c-Myb expression that controlled Bcl-2 and survival. These data define a role for TCF-1 in early-fate-bifurcation-driving Tex precursor cells and also identify PD-1 as a protector of this early TCF-1 subset.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Redes Reguladoras de Genes , Fator 1 de Transcrição de Linfócitos T/metabolismo , Transcrição Genética , Animais , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Doença Crônica , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Fator 1 de Transcrição de Linfócitos T/genética , Viroses/genética , Viroses/imunologia , Viroses/virologia
2.
Annu Rev Immunol ; 37: 457-495, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30676822

RESUMO

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, metabolic dysregulation, poor memory recall and homeostatic self-renewal, and distinct transcriptional and epigenetic programs. The ability to reinvigorate Tex cells through inhibitory receptor blockade, such as αPD-1, highlights the therapeutic potential of targeting this population. Emerging insights into the mechanisms of exhaustion are informing immunotherapies for cancer and chronic infections. However, like other immune cells, Tex cells are heterogeneous and include progenitor and terminal subsets with unique characteristics and responses to checkpoint blockade. Here, we review our current understanding of Tex cell biology, including the developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors contributing to exhaustion and how this knowledge may inform therapeutic targeting of Tex cells in chronic infections, autoimmunity, and cancer.


Assuntos
Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Imunoterapia/métodos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/fisiologia , Viroses/imunologia , Animais , Senescência Celular , Doença Crônica , Anergia Clonal , Epigênese Genética , Humanos , Neoplasias/terapia , Viroses/terapia
3.
Cell Rep ; 23(7): 2142-2156, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29768211

RESUMO

Persistent viral infections and tumors drive development of exhausted T (TEX) cells. In these settings, TEX cells establish an important host-pathogen or host-tumor stalemate. However, TEX cells erode over time, leading to loss of pathogen or cancer containment. We identified microRNA (miR)-155 as a key regulator of sustained TEX cell responses during chronic lymphocytic choriomeningitis virus (LCMV) infection. Genetic deficiency of miR-155 ablated CD8 T cell responses during chronic infection. Conversely, enhanced miR-155 expression promoted expansion and long-term persistence of TEX cells. However, rather than strictly antagonizing exhaustion, miR-155 promoted a terminal TEX cell subset. Transcriptional profiling identified coordinated control of cell signaling and transcription factor pathways, including the key AP-1 family member Fosl2. Overexpression of Fosl2 reversed the miR-155 effects, identifying a link between miR-155 and the AP-1 transcriptional program in regulating TEX cells. Thus, we identify a mechanism of miR-155 regulation of TEX cells and a key role for Fosl2 in T cell exhaustion.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Doenças Transmissíveis/genética , Doenças Transmissíveis/imunologia , MicroRNAs/metabolismo , Animais , Diferenciação Celular , Proliferação de Células/genética , Doença Crônica , Doenças Transmissíveis/patologia , Antígeno 2 Relacionado a Fos/metabolismo , Regulação da Expressão Gênica , Subpopulações de Linfócitos/imunologia , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Fenótipo , Fatores de Tempo , Fator de Transcrição AP-1/metabolismo , Transcrição Genética
4.
PLoS Pathog ; 14(4): e1006973, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29652923

RESUMO

CD4+ T cells subsets have a wide range of important helper and regulatory functions in the immune system. Several studies have specifically suggested that circulating effector CD4+ T cells may play a direct role in control of HIV replication through cytolytic activity or autocrine ß-chemokine production. However, it remains unclear whether effector CD4+ T cells expressing cytolytic molecules and ß-chemokines are present within lymph nodes (LNs), a major site of HIV replication. Here, we report that expression of ß-chemokines and cytolytic molecules are enriched within a CD4+ T cell population with high levels of the T-box transcription factors T-bet and eomesodermin (Eomes). This effector population is predominately found in peripheral blood and is limited in LNs regardless of HIV infection or treatment status. As a result, CD4+ T cells generally lack effector functions in LNs, including cytolytic capacity and IFNγ and ß-chemokine expression, even in HIV elite controllers and during acute/early HIV infection. While we do find the presence of degranulating CD4+ T cells in LNs, these cells do not bear functional or transcriptional effector T cell properties and are inherently poor to form stable immunological synapses compared to their peripheral blood counterparts. We demonstrate that CD4+ T cell cytolytic function, phenotype, and programming in the peripheral blood is dissociated from those characteristics found in lymphoid tissues. Together, these data challenge our current models based on blood and suggest spatially and temporally dissociated mechanisms of viral control in lymphoid tissues.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Vigilância Imunológica , Linfonodos/imunologia , Tecido Linfoide/imunologia , Linfócitos T CD4-Positivos/virologia , Estudos de Casos e Controles , Infecções por HIV/virologia , Humanos , Linfonodos/virologia , Tecido Linfoide/virologia , Carga Viral
5.
Nat Protoc ; 12(9): 1980-1998, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28858287

RESUMO

Retroviral (RV) expression of genes of interest (GOIs) is an invaluable tool and has formed the foundation of cellular engineering for adoptive cell therapy in cancer and other diseases. However, monitoring of transduced T cells long term (weeks to months) in vivo remains challenging because of the low frequency and often poor durability of transduced T cells over time when transferred without enrichment. Traditional methods often require additional overnight in vitro culture after transduction. Moreover, in vitro-generated effector CD8+ T cells enriched by sorting often have reduced viability, making it difficult to monitor the fate of transferred cells in vivo. Here, we describe an optimized mouse CD8+ T-cell RV transduction protocol that uses simple and rapid Percoll density centrifugation to enrich RV-susceptible activated CD8+ T cells. Percoll density centrifugation is simple, can be done on the day of transduction, requires minimal time, has low reagent costs and improves cell recovery (up to 60%), as well as the frequency of RV-transduced cells (∼sixfold over several weeks in vivo as compared with traditional methods). We have used this protocol to assess the long-term stability of CD8+ T cells after RV transduction by comparing the durability of T cells transduced with retroviruses expressing each of six commonly used RV reporter genes. Thus, we provide an optimized enrichment and transduction approach that allows long-term in vivo assessment of RV-transduced T cells. The overall procedure from T-cell isolation to RV transduction takes 2 d, and enrichment of activated T cells can be done in 1 h.


Assuntos
Linfócitos T CD8-Positivos/virologia , Vetores Genéticos/genética , Retroviridae/genética , Transdução Genética/métodos , Animais , Camundongos
6.
Front Immunol ; 7: 337, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27610109

RESUMO

[This corrects the article on p. 217 in vol. 5, PMID: 24860576.].

7.
Immunity ; 45(2): 358-73, 2016 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-27496729

RESUMO

Dynamic reprogramming of metabolism is essential for T cell effector function and memory formation. However, the regulation of metabolism in exhausted CD8(+) T (Tex) cells is poorly understood. We found that during the first week of chronic lymphocytic choriomeningitis virus (LCMV) infection, before severe dysfunction develops, virus-specific CD8(+) T cells were already unable to match the bioenergetics of effector T cells generated during acute infection. Suppression of T cell bioenergetics involved restricted glucose uptake and use, despite persisting mechanistic target of rapamycin (mTOR) signaling and upregulation of many anabolic pathways. PD-1 regulated early glycolytic and mitochondrial alterations and repressed transcriptional coactivator PGC-1α. Improving bioenergetics by overexpression of PGC-1α enhanced function in developing Tex cells. Therapeutic reinvigoration by anti-PD-L1 reprogrammed metabolism in a subset of Tex cells. These data highlight a key metabolic control event early in exhaustion and suggest that manipulating glycolytic and mitochondrial metabolism might enhance checkpoint blockade outcomes.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Animais , Anticorpos Neutralizantes/farmacologia , Antígeno B7-H1/imunologia , Células Cultivadas , Reprogramação Celular , Senescência Celular , Metabolismo Energético , Glucose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Receptor de Morte Celular Programada 1/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
8.
Front Immunol ; 5: 217, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24860576

RESUMO

The T-box transcription factors T-bet and Eomesodermin (Eomes) have been well defined as key drivers of immune cell development and cytolytic function. While the majority of studies have defined the roles of these factors in the context of murine T-cells, recent results have revealed that T-bet, and possibly Eomes, are expressed in other immune cell subsets. To date, the expression patterns of these factors in subsets of human peripheral blood mononuclear cells beyond T-cells remain relatively uncharacterized. In this study, we used multiparametric flow cytometry to characterize T-bet and Eomes expression in major human blood cell subsets, including total CD4(+) and CD8(+) T-cells, γδ T-cells, invariant NKT cells, natural killer cells, B-cells, and dendritic cells. Our studies identified novel cell subsets that express T-bet and Eomes and raise implications for their possible functions in the context of other human immune cell subsets besides their well-known roles in T-cells.

9.
Genes Dev ; 27(13): 1511-25, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23824541

RESUMO

Bunyaviruses are an emerging group of medically important viruses, many of which are transmitted from insects to mammals. To identify host factors that impact infection, we performed a genome-wide RNAi screen in Drosophila and identified 131 genes that impacted infection of the mosquito-transmitted bunyavirus Rift Valley fever virus (RVFV). Dcp2, the catalytic component of the mRNA decapping machinery, and two decapping activators, DDX6 and LSM7, were antiviral against disparate bunyaviruses in both insect cells and adult flies. Bunyaviruses 5' cap their mRNAs by "cap-snatching" the 5' ends of poorly defined host mRNAs. We found that RVFV cap-snatches the 5' ends of Dcp2 targeted mRNAs, including cell cycle-related genes. Loss of Dcp2 allows increased viral transcription without impacting viral mRNA stability, while ectopic expression of Dcp2 impedes viral transcription. Furthermore, arresting cells in late S/early G2 led to increased Dcp2 mRNA targets and increased RVFV replication. Therefore, RVFV competes for the Dcp2-accessible mRNA pool, which is dynamically regulated and can present a bottleneck for viral replication.


Assuntos
Drosophila melanogaster/genética , Drosophila melanogaster/virologia , Genoma de Inseto/genética , Orthobunyavirus/fisiologia , Capuzes de RNA/metabolismo , Fatores de Transcrição , Replicação Viral/fisiologia , Aedes/virologia , Animais , Pontos de Checagem do Ciclo Celular , Linhagem Celular , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Regulação da Expressão Gênica , Capuzes de RNA/genética , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
J Immunol ; 190(7): 3207-15, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23455505

RESUMO

In mice, two T-box transcription factors, T-box expressed in T cells (T-bet) and eomesodermin (Eomes), drive the differentiation of CD8 T cell lineages; however, little is known regarding their role in human CD8 T cell differentiation. In this study, we characterized T-bet and Eomes expression and localization within human CD8 memory T cell populations. We find that T-bet and Eomes are broadly expressed in human memory CD8 T cells, with increasing levels of T-bet and Eomes strongly correlating with differentiation from central memory to effector memory and effector subpopulations. In resting T cells, T-bet levels directly correlate to subcellular localization, with a higher propensity for nuclear expression of T-bet within T-bet(hi) cells and predominantly cytoplasmic expression in T-bet(lo) cells. In addition, Eomes is also localized to either the nucleus or the cytoplasm. Upon TCR stimulation, the percentage of T cells that express T-bet dramatically increases, whereas the percentage of cells expressing Eomes remains largely unchanged across all memory populations. Of interest, T-bet, but not Eomes, relocalizes to the nucleus in the majority of cells across all populations within 24 h post stimulation. These data indicate that T-bet and Eomes are likely regulated at the level of subcellular localization, potentially via different mechanisms. Together, these findings suggest a novel model for CD8 T cell differentiation in humans that is based on the localization of T-bet and Eomes.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Memória Imunológica , Proteínas com Domínio T/metabolismo , Núcleo Celular/metabolismo , Células Cultivadas , Humanos , Imunofenotipagem , Ativação Linfocitária/imunologia , Fenótipo , Transporte Proteico , Receptores de Antígenos de Linfócitos T/metabolismo
11.
Traffic ; 11(3): 311-23, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20028483

RESUMO

Nuclear localization signals (NLSs) are amino acid sequences that target cargo proteins into the nucleus. Rigorous characterization of NLS motifs is essential to understanding and predicting pathways for nuclear import. The best-characterized NLS is the classical NLS (cNLS), which is recognized by the cNLS receptor, importin-alpha. cNLSs are conventionally defined as having one (monopartite) or two clusters of basic amino acids separated by a 9-12 aa linker (bipartite). Motivated by the finding that Ty1 integrase, which contains an unconventional putative bipartite cNLS with a 29 aa linker, exploits the classical nuclear import machinery, we assessed the functional boundaries for linker length within a bipartite cNLS. We confirmed that the integrase cNLS is a bona fide bipartite cNLS, then carried out a systematic analysis of linker length in an obligate bipartite cNLS cargo, which revealed that some linkers longer than conventionally defined can function in nuclear import. Linker function is dependent on the sequence and likely the inherent flexibility of the linker. Subsequently, we interrogated the Saccharomyces cerevisiae proteome to identify cellular proteins containing putative long bipartite cNLSs. We experimentally confirmed that Rrp4 contains a bipartite cNLS with a 25 aa linker. Our studies show that the traditional definition of bipartite cNLSs is too restrictive and linker length can vary depending on amino acid composition.


Assuntos
Sinais de Localização Nuclear/metabolismo , Proteoma , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Transporte Ativo do Núcleo Celular , Sequência de Aminoácidos , Integrases/metabolismo , Carioferinas/metabolismo , Dados de Sequência Molecular
12.
IUBMB Life ; 61(7): 697-706, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19514019

RESUMO

In eukaryotic cells, the physical separation of the genetic material in the nucleus from the translation and signaling machinery in the cytoplasm by the nuclear envelope creates a requirement for a mechanism through which macromolecules can enter or exit the nucleus as necessary. Nucleocytoplasmic transport involves the specific recognition of cargo molecules by transport receptors in one compartment followed by the physical relocation of that cargo into the other compartment through regulated pores that perforate the nuclear envelope. The recognition of protein cargoes by their transport receptors occurs via amino acid sequences in cargo proteins called nuclear targeting signals. Both nuclear import and export of proteins are highly regulated processes that control, not only what cargo can enter and/or exit the nucleus, but also when in the cell cycle and in what cell type, the cargo can be transported. Deregulation of the nuclear transport of specific cargoes has been linked to numerous cancers and developmental disorders highlighting the importance of understanding the mechanisms underlying nucleocytoplasmic transport and particularly the modulation of the specific interactions between transporter receptors and nuclear targeting signals within target cargo proteins.


Assuntos
Transporte Ativo do Núcleo Celular/fisiologia , Sinais de Localização Nuclear/fisiologia , Motivos de Aminoácidos/fisiologia , Sequência de Aminoácidos , Humanos , Fatores de Transcrição NFATC/fisiologia , Membrana Nuclear/metabolismo , Poro Nuclear/fisiologia
13.
Genetics ; 181(1): 105-18, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18984568

RESUMO

There is significant evidence linking nucleocytoplasmic transport to cell cycle control. The budding yeast, Saccharomyces cerevisiae, serves as an ideal model system for studying transport events critical to cell cycle progression because the nuclear envelope remains intact throughout the cell cycle. Previous studies linked the classical nuclear localization signal (cNLS) receptor, importin-alpha/Srp1, to the G(2)/M transition of the cell cycle. Here, we utilize two engineered mutants of importin-alpha/Srp1 with specific molecular defects to explore how protein import affects cell cycle progression. One mutant, Srp1-E402Q, is defective in binding to cNLS cargoes that contain two clusters of basic residues termed a bipartite cNLS. The other mutant, Srp1-55, has defects in release of cNLS cargoes into the nucleus. Consistent with distinct in vivo functional consequences for each of the Srp1 mutants analyzed, we find that overexpression of different nuclear transport factors can suppress the temperature-sensitive growth defects of each mutant. Studies aimed at understanding how each of these mutants affects cell cycle progression reveal a profound defect at the G(1) to S phase transition in both srp1-E402Q and srp1-55 mutants as well as a modest G(1)/S defect in the temperature-sensitive srp1-31 mutant, which was previously implicated in G(2)/M. We take advantage of the characterized defects in the srp1-E402Q and srp1-55 mutants to predict candidate cargo proteins likely to be affected in these mutants and provide evidence that three of these cargoes, Cdc45, Yox1, and Mcm10, are not efficiently localized to the nucleus in importin-alpha mutants. These results reveal that the classical nuclear protein import pathway makes important contributions to the G(1)/S cell cycle transition.


Assuntos
Fase G1 , Carioferinas/metabolismo , Sinais de Localização Nuclear/metabolismo , Fase S , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/citologia , alfa Carioferinas/metabolismo , Transporte Ativo do Núcleo Celular , Núcleo Celular/metabolismo , Genes Supressores , Proteínas de Fluorescência Verde/metabolismo , Proteínas Mutantes/metabolismo , Mutação/genética , Plasmídeos/genética , Saccharomyces cerevisiae/genética
14.
Nucleic Acids Res ; 36(13): 4317-26, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18586821

RESUMO

Like its retroviral relatives, the long terminal repeat retrotransposon Ty1 in the yeast Saccharomyces cerevisiae must traverse a permanently intact nuclear membrane for successful transposition and replication. For retrotransposition to occur, at least a subset of Ty1 proteins, including the Ty1 integrase, must enter the nucleus. Nuclear localization of integrase is dependent upon a C-terminal nuclear targeting sequence. However, the nuclear import machinery that recognizes this nuclear targeting signal has not been defined. We investigated the mechanism by which Ty1 integrase gains access to nuclear DNA as a model for how other retroelements, including retroviruses like HIV, may utilize cellular nuclear transport machinery to import their essential nuclear proteins. We show that Ty1 retrotransposition is significantly impaired in yeast mutants that alter the classical nuclear protein import pathway, including the Ran-GTPase, and the dimeric import receptor, importin-alpha/beta. Although Ty1 proteins are made and processed in these mutant cells, our studies reveal that an integrase reporter is not properly targeted to the nucleus in cells carrying mutations in the classical nuclear import machinery. Furthermore, we demonstrate that integrase coimmunoprecipitates with the importin-alpha transport receptor and directly binds to importin-alpha. Taken together, these data suggest Ty1 integrase can employ the classical nuclear protein transport machinery to enter the nucleus.


Assuntos
Núcleo Celular/metabolismo , Integrases/metabolismo , Proteínas Nucleares/metabolismo , Retroelementos , Proteínas de Saccharomyces cerevisiae/metabolismo , Transporte Ativo do Núcleo Celular , Núcleo Celular/química , Citoplasma/química , Proteínas de Fluorescência Verde/análise , Integrases/química , Mutação , Sinais de Localização Nuclear , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , alfa Carioferinas/genética , alfa Carioferinas/metabolismo , Proteína ran de Ligação ao GTP/genética , Proteína ran de Ligação ao GTP/metabolismo
15.
Nucleic Acids Res ; 35(20): 6862-9, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17933776

RESUMO

Gene expression is controlled by RNA-binding proteins that modulate the synthesis, processing, transport and stability of various classes of RNA. Some RNA-binding proteins shuttle between the nucleus and cytoplasm and are thought to bind to RNA transcripts in the nucleus and remain bound during translocation to the cytoplasm. One RNA-binding protein that has been hypothesized to function in this manner is the Saccharomyces cerevisiae Scp160 protein. Although the steady-state localization of Scp160 is cytoplasmic, previous studies have identified putative nuclear localization (NLS) and nuclear export (NES) signals. The goal of this study was to test the hypothesis that Scp160 is a nucleocytoplasmic shuttling protein. We exploited a variety of yeast export mutants to capture any potential nuclear accumulation of Scp160 and found no evidence that Scp160 enters the nucleus. These localization studies were complemented by a mutational analysis of the predicted NLS. Results indicate that key basic residues within the predicted NLS of Scp160 can be altered without severely affecting Scp160 function. This finding has important implications for understanding the function of Scp160, which is likely limited to the cytoplasm. Additionally, our results provide strong evidence that the presence of a predicted nuclear localization signal within the sequence of a protein should not lead to the assumption that the protein enters the nucleus in the absence of additional experimental evidence.


Assuntos
Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Sinais de Localização Nuclear/análise , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Núcleo Celular/metabolismo , Citoplasma/química , Citoplasma/metabolismo , Proteínas de Fluorescência Verde/análise , Proteínas de Membrana/genética , Mutagênese Sítio-Dirigida , Proteínas Nucleares/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/química , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética
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