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1.
Cell Rep ; 37(6): 109968, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34758326

RESUMO

N6-methyladenosine (m6A) RNA modification is a fundamental determinant of mRNA metabolism, but its role in innate immunity-driven non-alcoholic fatty liver disease (NAFLD) and obesity is not known. Here, we show that myeloid lineage-restricted deletion of the m6A "writer" protein Methyltransferase Like 3 (METTL3) prevents age-related and diet-induced development of NAFLD and obesity in mice with improved inflammatory and metabolic phenotypes. Mechanistically, loss of METTL3 results in the differential expression of multiple mRNA transcripts marked with m6A, with a notable increase of DNA Damage Inducible Transcript 4 (DDIT4) mRNA level. In METTL3-deficient macrophages, there is a significant downregulation of mammalian target of rapamycin (mTOR) and nuclear factor κB (NF-κB) pathway activity in response to cellular stress and cytokine stimulation, which can be restored by knockdown of DDIT4. Taken together, our findings identify the contribution of METTL3-mediated m6A modification of Ddit4 mRNA to macrophage metabolic reprogramming in NAFLD and obesity.

2.
Nat Commun ; 12(1): 5522, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535671

RESUMO

Natural killer (NK) cells exert critical roles in anti-tumor immunity but how their functions are regulated by epitranscriptional modification (e.g., N6-methyladenosine (m6A) methylation) is unclear. Here we report decreased expression of the m6A "writer" METTL3 in tumor-infiltrating NK cells, and a positive correlation between protein expression levels of METTL3 and effector molecules in NK cells. Deletion of Mettl3 in NK cells alters the homeostasis of NK cells and inhibits NK cell infiltration and function in the tumor microenvironment, leading to accelerated tumor development and shortened survival in mice. The gene encoding SHP-2 is m6A modified, and its protein expression is decreased in METTL3-deficient NK cells. Reduced SHP-2 activity renders NK cells hyporesponsive to IL-15, which is associated with suppressed activation of the AKT and MAPK signaling pathway in METTL3-deficient NK cells. These findings show that m6A methylation safeguards the homeostasis and tumor immunosurveillance function of NK cells.


Assuntos
Adenosina/análogos & derivados , Células Matadoras Naturais/imunologia , Metiltransferases/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , RNA/metabolismo , Adenosina/metabolismo , Animais , Carcinogênese/patologia , Linhagem Celular Tumoral , Deleção de Genes , Homeostase , Interleucina-15/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Metilação , Metiltransferases/deficiência , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Microambiente Tumoral
3.
Psychiatry Res Neuroimaging ; 316: 111344, 2021 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-34358964

RESUMO

Schizophrenia is characterized by both disrupted neurodevelopmental processes and abnormal brain connectivity. However, few studies have examined the atypical features of brain network topography associated with schizophrenia during childhood and adolescence. We used graph theory to compare the grey matter structural networks of individuals (aged 10-15 years) with early-onset schizophrenia (EOS) (n = 25) and a typically-developing (TD) comparison group (n = 31). Compared with the TD group, EOS patients showed significantly increased clustering and local efficiency across a range of network densities (0.3 - 0.4). The network of EOS patients also had more modules (6 modules in EOS vs. 3 modules in controls), indicating a more segregated network at the cost of functional integration. Although our results were preliminary and failed to survive corrections for multiple comparisons, EOS patients might be characterized by altered nodal centrality in several higher-order associative regions including the prefrontal cortex, the hippocampus and the cerebellum. The EOS structural network also lacked the typical left-hemispheric-dominant hub distribution compared with the TD group. These findings suggest that brain structural network was not only globally but also regionally altered in EOS patients.


Assuntos
Substância Cinzenta , Esquizofrenia , Adolescente , Encéfalo/diagnóstico por imagem , Córtex Cerebral , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Esquizofrenia/diagnóstico por imagem
4.
Sci Adv ; 7(25)2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34134995

RESUMO

N6-methyladenosine (m6A) modification is dynamically regulated by "writer" and "eraser" enzymes. m6A "writers" have been shown to ensure the homeostasis of CD4+ T cells, but the "erasers" functioning in T cells is poorly understood. Here, we reported that m6A eraser AlkB homolog 5 (ALKBH5), but not FTO, maintains the ability of naïve CD4+ T cells to induce adoptive transfer colitis. In addition, T cell-specific ablation of ALKBH5 confers protection against experimental autoimmune encephalomyelitis. During the induced neuroinflammation, ALKBH5 deficiency increased m6A modification on interferon-γ and C-X-C motif chemokine ligand 2 messenger RNA (mRNA), thus decreasing their mRNA stability and protein expression in CD4+ T cells. These modifications resulted in attenuated CD4+ T cell responses and diminished recruitment of neutrophils into the central nervous system. Our findings reveal an unexpected specific role of ALKBH5 as an m6A eraser in controlling the pathogenicity of CD4+ T cells during autoimmunity.

5.
Front Immunol ; 12: 627455, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912158

RESUMO

RNA modification represents one of the most ubiquitous mechanisms of epigenetic regulation and plays an essential role in modulating cell proliferation, differentiation, fate determination, and other biological activities. At present, over 170 types of RNA modification have been discovered in messenger RNA (mRNA) and noncoding RNA (ncRNA). RNA methylation, as an abundant and widely studied epigenetic modification, is crucial for regulating various physiological or pathological states, especially immune responses. Considering the biological significance of T cells as a defense against viral infection and tumor challenge, in this review, we will summarize recent findings of how RNA methylation regulates T cell homeostasis and function, discuss the open questions in this rapidly expanding field of RNA modification, and provide the theoretical basis and potential therapeutic strategies involving targeting of RNA methylation to orchestrate beneficial T cell immune responses.


Assuntos
Processamento Pós-Transcricional do RNA , RNA/metabolismo , Linfócitos T/imunologia , Adenina/análogos & derivados , Adenina/metabolismo , Epigênese Genética , Humanos , Metilação , Metiltransferases/fisiologia
6.
Sci Adv ; 7(18)2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33910903

RESUMO

m6A RNA modification is implicated in multiple cellular responses. However, its function in the innate immune cells is poorly understood. Here, we identified major m6A "writers" as the top candidate genes regulating macrophage activation by LPS in an RNA binding protein focused CRISPR screening. We have confirmed that Mettl3-deficient macrophages exhibited reduced TNF-α production upon LPS stimulation in vitro. Consistently, Mettl3 flox/flox;Lyzm-Cre mice displayed increased susceptibility to bacterial infection and showed faster tumor growth. Mechanistically, the transcripts of the Irakm gene encoding a negative regulator of TLR4 signaling were highly decorated by m6A modification. METTL3 deficiency led to the loss of m6A modification on Irakm mRNA and slowed down its degradation, resulting in a higher level of IRAKM, which ultimately suppressed TLR signaling-mediated macrophage activation. Our findings demonstrate a previously unknown role for METTL3-mediated m6A modification in innate immune responses and implicate the m6A machinery as a potential cancer immunotherapy target.

7.
Nature ; 592(7855): 606-610, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33658717

RESUMO

Intestinal stromal cells are known to modulate the propagation and differentiation of intestinal stem cells1,2. However, the precise cellular and molecular mechanisms by which this diverse stromal cell population maintains tissue homeostasis and repair are poorly understood. Here we describe a subset of intestinal stromal cells, named MAP3K2-regulated intestinal stromal cells (MRISCs), and show that they are the primary cellular source of the WNT agonist R-spondin 1 following intestinal injury in mice. MRISCs, which are epigenetically and transcriptomically distinct from subsets of intestinal stromal cells that have previously been reported3-6, are strategically localized at the bases of colon crypts, and function to maintain LGR5+ intestinal stem cells and protect against acute intestinal damage through enhanced R-spondin 1 production. Mechanistically, this MAP3K2 specific function is mediated by a previously unknown reactive oxygen species (ROS)-MAP3K2-ERK5-KLF2 axis to enhance production of R-spondin 1. Our results identify MRISCs as a key component of an intestinal stem cell niche that specifically depends on MAP3K2 to augment WNT signalling for the regeneration of damaged intestine.

8.
Mol Cancer ; 20(1): 29, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33557837

RESUMO

BACKGROUND: The four major RNA adenosine modifications, i.e., m6A, m1A, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the "writer" enzymes and constitute critical mechanisms of epigenetic regulation in immune response and tumorigenesis. However, the cross-talk and potential roles of these "writers" in the tumor microenvironment (TME), drug sensitivity, and immunotherapy remain unknown. METHODS: We systematically characterized mRNA expression and genetic alterations of 26 RNA modification "writers" in colorectal cancer (CRC), and evaluated their expression pattern in 1697 CRC samples from 8 datasets. We used an unsupervised clustering method to assign the samples into two patterns of expression of RNA modification "writers". Subsequently, we constructed the RNA modification "writer" Score (WM_Score) model based on differentially expressed genes (DEGs) responsible for the RNA modification patterns to quantify the RNA modification-related subtypes of individual tumors. Furthermore, we performed association analysis for WM_Score and characteristics of TME, consensus molecular subtypes (CMSs), clinical features, transcriptional and post-transcriptional regulation, drug response, and the efficacy of immunotherapy. RESULTS: We demonstrated that multi-layer alterations of RNA modification "writer" are associated with patient survival and TME cell-infiltrating characteristics. We identified two distinct RNA modification patterns, characterized by a high and a low WM_Score. The WM_Score-high group was associated with worse patient overall survival and with the infiltration of inhibitory immune cells, such as M2 macrophages, EMT activation, and metastasis, while the WM_Score-low group was associated with a survival advantage, apoptosis, and cell cycle signaling pathways. WM_Score correlated highly with the regulation of transcription and post-transcriptional events contributing to the development of CRC. In response to anti-cancer drugs, WM_Score highly negatively correlated (drug sensitive) with drugs which targeted oncogenic related pathways, such as MAPK, EGFR, and mTOR signaling pathways, positively correlated (drug resistance) with drugs which targeted in apoptosis and cell cycle. Importantly, the WM_Score was associated with the therapeutic efficacy of PD-L1 blockade, suggesting that the development of potential drugs targeting these "writers" to aid the clinical benefits of immunotherapy. CONCLUSIONS: Our study is the first to provide a comprehensive analysis of four RNA modifications in CRC. We revealed the potential function of these writers in TME, transcriptional and post-transcriptional events, and identified their therapeutic liability in targeted therapy and immunotherapy. This work highlights the cross-talk and potential clinical utility of RNA modification "writers" in cancer therapy.


Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Farmacogenética , Processamento Pós-Transcricional do RNA , Microambiente Tumoral/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Terapia Combinada , Biologia Computacional/métodos , Gerenciamento Clínico , Suscetibilidade a Doenças , Transição Epitelial-Mesenquimal , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Farmacogenética/métodos , Prognóstico , Modelos de Riscos Proporcionais , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , Transcrição Genética , Transcriptoma , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
9.
Proc Natl Acad Sci U S A ; 118(4)2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33483420

RESUMO

RNA helicases play roles in various essential biological processes such as RNA splicing and editing. Recent in vitro studies show that RNA helicases are involved in immune responses toward viruses, serving as viral RNA sensors or immune signaling adaptors. However, there is still a lack of in vivo data to support the tissue- or cell-specific function of RNA helicases owing to the lethality of mice with complete knockout of RNA helicases; further, there is a lack of evidence about the antibacterial role of helicases. Here, we investigated the in vivo role of Dhx15 in intestinal antibacterial responses by generating mice that were intestinal epithelial cell (IEC)-specific deficient for Dhx15 (Dhx15 f/f Villin1-cre, Dhx15ΔIEC). These mice are susceptible to infection with enteric bacteria Citrobacter rodentium (C. rod), owing to impaired α-defensin production by Paneth cells. Moreover, mice with Paneth cell-specific depletion of Dhx15 (Dhx15 f/f Defensinα6-cre, Dhx15ΔPaneth) are more susceptible to DSS (dextran sodium sulfate)-induced colitis, which phenocopy Dhx15ΔIEC mice, due to the dysbiosis of the intestinal microbiota. In humans, reduced protein levels of Dhx15 are found in ulcerative colitis (UC) patients. Taken together, our findings identify a key regulator of Wnt-induced α-defensins in Paneth cells and offer insights into its role in the antimicrobial response as well as intestinal inflammation.


Assuntos
Colite/imunologia , Defensinas/genética , Infecções por Enterobacteriaceae/imunologia , Celulas de Paneth/imunologia , RNA Helicases/genética , Via de Sinalização Wnt , Animais , Citrobacter rodentium/imunologia , Citrobacter rodentium/patogenicidade , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Defensinas/imunologia , Sulfato de Dextrana/administração & dosagem , Infecções por Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Microbioma Gastrointestinal/imunologia , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/imunologia , Celulas de Paneth/microbiologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , RNA Helicases/imunologia
11.
Immunity ; 52(6): 1007-1021.e8, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32497523

RESUMO

N6-methyladenosine (m6A) is the most abundant RNA modification, but little is known about its role in mammalian hematopoietic development. Here, we show that conditional deletion of the m6A writer METTL3 in murine fetal liver resulted in hematopoietic failure and perinatal lethality. Loss of METTL3 and m6A activated an aberrant innate immune response, mediated by the formation of endogenous double-stranded RNAs (dsRNAs). The aberrantly formed dsRNAs were long, highly m6A modified in their native state, characterized by low folding energies, and predominantly protein coding. We identified coinciding activation of pattern recognition receptor pathways normally tasked with the detection of foreign dsRNAs. Disruption of the aberrant immune response via abrogation of downstream Mavs or Rnasel signaling partially rescued the observed hematopoietic defects in METTL3-deficient cells in vitro and in vivo. Our results suggest that m6A modification protects against endogenous dsRNA formation and a deleterious innate immune response during mammalian hematopoietic development.


Assuntos
Adenosina/química , Hematopoese/genética , Hematopoese/imunologia , Imunidade Inata/genética , RNA de Cadeia Dupla/metabolismo , Animais , Biomarcadores , Transtornos da Insuficiência da Medula Óssea/etiologia , Transtornos da Insuficiência da Medula Óssea/metabolismo , Transtornos da Insuficiência da Medula Óssea/patologia , Diferenciação Celular/genética , Modelos Animais de Doenças , Epigênese Genética , Expressão Gênica , Células-Tronco Hematopoéticas , Imunofenotipagem , Metilação , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Camundongos Knockout , RNA de Cadeia Dupla/química
12.
Asian J Psychiatr ; 53: 102167, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32474345

RESUMO

Empathy refers to the ability to understand other people's feelings and reacting emotionally to others. Impaired empathy has been reported in both individuals with schizophrenia and autism spectrum disorders (ASD). Despite overlaps, few studies have directly examined the neural mechanisms of impaired empathy in these two clinical groups. We used resting-state fMRI to investigate the neural correlates of empathic functioning in adolescents with ASD (N = 11), early-onset schizophrenia (EOS) (N = 20), and typically developing (TD) controls (N = 26). Their parents completed the Griffith Empathy Measure (GEM) to assess the adolescents' empathic capacity. We found that EOS and ASD participants both exhibited impaired empathy as measured by the GEM, especially in cognitive empathy (post-hoc ps < 0.05). Regions-of-interest-based functional connectivity revealed decreased connectivity between the salience network (SN) (i.e., the anterior insula and the anterior cingulate cortex) and core regions of the mentalizing network (e.g., the temporal-parietal junction and the precuneus), and among the SN and the bilateral superior temporal gyri (STG) and the left cerebellum in EOS participants. Subsequent comparisons revealed reduced grey matter volume in the STG bilaterally in both clinical groups. Increased resting-state functional connectivity within the social brain network was correlated with higher parent-reported scores of empathic capacity in TD adolescents, but such a brain-phenotype relationship was absent in the two clinical groups. These findings indicate that structural alterations and disturbed resting-state functional connectivity in the core empathy network may be the neural correlates of social cognitive deficits in individuals with EOS and ASD.


Assuntos
Transtorno do Espectro Autista , Esquizofrenia , Adolescente , Transtorno do Espectro Autista/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Empatia , Humanos , Imageamento por Ressonância Magnética , Vias Neurais/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem
13.
Science ; 367(6483): 1255-1260, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32165587

RESUMO

T cells maintain a quiescent state prior to activation. As inappropriate T cell activation can cause disease, T cell quiescence must be preserved. Despite its importance, the mechanisms underlying the "quiescent state" remain elusive. Here, we identify BTG1 and BTG2 (BTG1/2) as factors responsible for T cell quiescence. BTG1/2-deficient T cells show an increased proliferation and spontaneous activation due to a global increase in messenger RNA (mRNA) abundance, which reduces the threshold to activation. BTG1/2 deficiency leads to an increase in polyadenylate tail length, resulting in a greater mRNA half-life. Thus, BTG1/2 promote the deadenylation and degradation of mRNA to secure T cell quiescence. Our study reveals a key mechanism underlying T cell quiescence and suggests that low mRNA abundance is a crucial feature for maintaining quiescence.


Assuntos
Proteínas Imediatamente Precoces/fisiologia , Ativação Linfocitária , Proteínas de Neoplasias/fisiologia , Estabilidade de RNA , RNA Mensageiro/química , Linfócitos T/imunologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Células Cultivadas , Proteínas Imediatamente Precoces/genética , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Poliadenilação , Proteínas Supressoras de Tumor/genética
15.
Cell Metab ; 30(2): 290-302.e5, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31204281

RESUMO

CD8+ T cell expansions and functions rely on glycolysis, but the mechanisms underlying CD8+ T cell glycolytic metabolism remain elusive. Here, we show that acylglycerol kinase (AGK) is required for the establishment and maintenance of CD8+ T cell metabolic and functional fitness. AGK deficiency dampens CD8+ T cell antitumor functions in vivo and perturbs CD8+ T cell proliferation in vitro. Activation of phosphatidylinositol-3-OH kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling, which mediates elevated CD8+ T cell glycolysis, is tightly dependent on AGK kinase activity. Mechanistically, T cell antigen receptor (TCR)- and CD28-stimulated recruitment of PTEN to the plasma membrane facilitates AGK-PTEN interaction and AGK-triggered PTEN phosphorylation, thereby restricting PTEN phosphatase activity in CD8+ T cells. Collectively, these results demonstrate that AGK maintains CD8+ T cell metabolic and functional state by restraining PTEN activity and highlight a critical role for AGK in CD8+ T cell metabolic programming and effector function.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/imunologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Animais , Feminino , Masculino , Melanoma Experimental/patologia , Camundongos , Camundongos Transgênicos
17.
18.
J Exp Med ; 215(9): 2463-2476, 2018 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-30115741

RESUMO

Metabolic programs are crucial for regulatory T (T reg) cell stability and function, but the underlying mechanisms that regulate T reg cell metabolism are elusive. Here, we report that lysosomal TRAF3IP3 acts as a pivotal regulator in the maintenance of T reg cell metabolic fitness. T reg-specific deletion of Traf3ip3 impairs T reg cell function, causing the development of inflammatory disorders and stronger antitumor T cell responses in mice. Excessive mechanistic target of rapamycin complex 1 (mTORC1)-mediated hyper-glycolytic metabolism is responsible for the instability of TRAF3IP3-deficient T reg cells. Mechanistically, TRAF3IP3 restricts mTORC1 signaling by recruiting the serine-threonine phosphatase catalytic subunit (PP2Ac) to the lysosome, thereby facilitating the interaction of PP2Ac with the mTORC1 component Raptor. Our results define TRAF3IP3 as a metabolic regulator in T reg cell stability and function and suggest a lysosome-specific mTORC1 signaling mechanism that regulates T reg cell metabolism.


Assuntos
Proteínas de Transporte , Glicólise , Lisossomos , Proteínas de Membrana , Transdução de Sinais , Linfócitos T Reguladores , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Glicólise/genética , Glicólise/imunologia , Lisossomos/genética , Lisossomos/imunologia , Lisossomos/metabolismo , Lisossomos/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Proteína Regulatória Associada a mTOR/genética , Proteína Regulatória Associada a mTOR/imunologia , Proteína Regulatória Associada a mTOR/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia
19.
Front Med ; 12(4): 481-489, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30097961

RESUMO

N6-methyladenosine (m6A) is the most common post-transcriptional RNA modification throughout the transcriptome, affecting fundamental aspects of RNA metabolism. m6A modification could be installed by m6A "writers" composed of core catalytic components (METTL3/METTL14/WTAP) and newly defined regulators and removed by m6A "erasers" (FTO and ALKBH5). The function of m6A is executed by m6A "readers" that bind to m6A directly (YTH domain-containing proteins, eIF3 and IGF2BPs) or indirectly (HNRNPA2B1). In the past few years, advances in m6A modulators ("writers," "erasers," and "readers") have remarkably renewed our understanding of the function and regulation of m6A in different cells under normal or disease conditions. However, the mechanism and the regulatory network of m6A are still largely unknown. Moreover, investigations of the m6A physiological roles in human diseases are limited. In this review, we summarize the recent advances in m6A research and highlight the functional relevance and importance of m6A modification in in vitro cell lines, in physiological contexts, and in cancers.


Assuntos
Adenosina/análogos & derivados , Neoplasias/metabolismo , Processamento Pós-Transcricional do RNA , RNA/metabolismo , Adenosina/metabolismo , Diferenciação Celular/fisiologia , Humanos
20.
Nat Commun ; 9(1): 3157, 2018 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-30089837

RESUMO

Regulatory T (Treg) cells are essential for maintaining immune homeostasis and tolerance, but the mechanisms regulating the stability and function of Treg cells have not been fully elucidated. Here we show SUMO-specific protease 3 (SENP3) is a pivotal regulator of Treg cells that functions by controlling the SUMOylation and nuclear localization of BACH2. Treg cell-specific deletion of Senp3 results in T cell activation, autoimmune symptoms and enhanced antitumor T cell responses. SENP3-mediated BACH2 deSUMOylation prevents the nuclear export of BACH2, thereby repressing the genes associated with CD4+ T effector cell differentiation and stabilizing Treg cell-specific gene signatures. Notably, SENP3 accumulation triggered by reactive oxygen species (ROS) is involved in Treg cell-mediated tumor immunosuppression. Our results not only establish the role of SENP3 in the maintenance of Treg cell stability and function via BACH2 deSUMOylation but also clarify the function of SENP3 in the regulation of ROS-induced immune tolerance.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Tolerância Imunológica/imunologia , Peptídeo Hidrolases/metabolismo , Sumoilação/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Antineoplásicos/metabolismo , Autoimunidade/imunologia , Células da Medula Óssea , Linfócitos T CD4-Positivos , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Núcleo Celular/imunologia , Cisteína Endopeptidases , Feminino , Deleção de Genes , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Células HEK293 , Homeostase/imunologia , Humanos , Ativação Linfocitária/imunologia , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptídeo Hidrolases/genética , Espécies Reativas de Oxigênio , Linfócitos T Reguladores/patologia
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