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1.
Autophagy ; 15(6): 1069-1081, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30653406

RESUMO

Protein arginine methyltransferases (PRMTs) have emerged as important regulators of skeletal muscle metabolism and regeneration. However, the direct roles of the various PRMTs during skeletal muscle remodeling remain unclear. Using skeletal muscle-specific prmt1 knockout mice, we examined the function and downstream targets of PRMT1 in muscle homeostasis. We found that muscle-specific PRMT1 deficiency led to muscle atrophy. PRMT1-deficient muscles exhibited enhanced expression of a macroautophagic/autophagic marker LC3-II, FOXO3 and muscle-specific ubiquitin ligases, TRIM63/MURF-1 and FBXO32, likely contributing to muscle atrophy. The mechanistic study reveals that PRMT1 regulates FOXO3 through PRMT6 modulation. In the absence of PRMT1, increased PRMT6 specifically methylates FOXO3 at arginine 188 and 249, leading to its activation. Finally, we demonstrate that PRMT1 deficiency triggers FOXO3 hyperactivation, which is abrogated by PRMT6 depletion. Taken together, PRMT1 is a key regulator for the PRMT6-FOXO3 axis in the control of autophagy and protein degradation underlying muscle maintenance. Abbreviations: Ad-RNAi: adenovirus-delivered small interfering RNA; AKT: thymoma viral proto-oncogene; AMPK: AMP-activated protein kinase; Baf A1: bafilomycin A1; CSA: cross-sectional area; EDL: extensor digitorum longus; FBXO32: F-box protein 32; FOXO: forkhead box O; GAS: gatrocnemieus; HDAC: histone deacetylase; IGF: insulin-like growth factor; LAMP: lysosomal-associated membrane protein; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mKO: Mice with skeletal muscle-specific deletion of Prmt1; MTOR: mechanistic target of rapamycin kinase; MYH: myosin heavy chain; MYL1/MLC1f: myosin, light polypeptide 1; PRMT: protein arginine N-methyltransferase; sgRNA: single guide RNA; SQSTM1: sequestosome 1; SOL: soleus; TA: tibialis anterior; TRIM63/MURF-1: tripartite motif-containing 63; YY1: YY1 transcription factor.

2.
Nat Commun ; 9(1): 5107, 2018 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-30504773

RESUMO

Dysregulation of Ca2+/calmodulin-dependent protein kinase (CaMK)II is closely linked with myocardial hypertrophy and heart failure. However, the mechanisms that regulate CaMKII activity are incompletely understood. Here we show that protein arginine methyltransferase 1 (PRMT1) is essential for preventing cardiac CaMKII hyperactivation. Mice null for cardiac PRMT1 exhibit a rapid progression to dilated cardiomyopathy and heart failure within 2 months, accompanied by cardiomyocyte hypertrophy and fibrosis. Consistently, PRMT1 is downregulated in heart failure patients. PRMT1 depletion in isolated cardiomyocytes evokes hypertrophic responses with elevated remodeling gene expression, while PRMT1 overexpression protects against pathological responses to neurohormones. The level of active CaMKII is significantly elevated in PRMT1-deficient hearts or cardiomyocytes. PRMT1 interacts with and methylates CaMKII at arginine residues 9 and 275, leading to its inhibition. Accordingly, pharmacological inhibition of CaMKII restores contractile function in PRMT1-deficient mice. Thus, our data suggest that PRMT1 is a critical regulator of CaMKII to maintain cardiac function.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Linhagem Celular , Ecocardiografia , Eletrocardiografia , Eletrofisiologia , Insuficiência Cardíaca/genética , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteína-Arginina N-Metiltransferases/genética
3.
Nat Chem Biol ; 12(7): 479-81, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27159578

RESUMO

Increasing the thermogenic activity of adipocytes holds promise as an approach to combating human obesity and related metabolic diseases. We identified induction of mouse PR domain containing 4 (Prdm4) by the small molecule butein as a means to induce expression of uncoupling protein 1 (Ucp1), increase energy expenditure, and stimulate the generation of thermogenic adipocytes. This study highlights a Prdm4-dependent pathway, modulated by small molecules, that stimulates browning of white adipose tissue.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Chalconas/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Chalconas/química , Proteínas de Ligação a DNA/metabolismo , Dieta Hiperlipídica/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Fatores de Transcrição/metabolismo
4.
Diabetes ; 65(1): 62-73, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26340929

RESUMO

The role of a glucagon/cAMP-dependent protein kinase-inducible coactivator PGC-1α signaling pathway is well characterized in hepatic gluconeogenesis. However, an opposing protein kinase B (PKB)/Akt-inducible corepressor signaling pathway is unknown. A previous report has demonstrated that small heterodimer partner-interacting leucine zipper protein (SMILE) regulates the nuclear receptors and transcriptional factors that control hepatic gluconeogenesis. Here, we show that hepatic SMILE expression was induced by feeding in normal mice but not in db/db and high-fat diet (HFD)-fed mice. Interestingly, SMILE expression was induced by insulin in mouse primary hepatocyte and liver. Hepatic SMILE expression was not altered by refeeding in liver-specific insulin receptor knockout (LIRKO) or PKB ß-deficient (PKBß(-/-)) mice. At the molecular level, SMILE inhibited hepatocyte nuclear factor 4-mediated transcriptional activity via direct competition with PGC-1α. Moreover, ablation of SMILE augmented gluconeogenesis and increased blood glucose levels in mice. Conversely, overexpression of SMILE reduced hepatic gluconeogenic gene expression and ameliorated hyperglycemia and glucose intolerance in db/db and HFD-fed mice. Therefore, SMILE is an insulin-inducible corepressor that suppresses hepatic gluconeogenesis. Small molecules that enhance SMILE expression would have potential for treating hyperglycemia in diabetes.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Ingestão de Alimentos/genética , Gluconeogênese/genética , Fator 4 Nuclear de Hepatócito/genética , Hepatócitos/metabolismo , Fígado/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Western Blotting , Linhagem Celular , Imunoprecipitação da Cromatina , Dieta Hiperlipídica , Expressão Gênica , Glucagon , Fator 4 Nuclear de Hepatócito/metabolismo , Hepatócitos/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-akt/genética , Receptor de Insulina/genética , Fatores de Transcrição/genética
5.
Sci Signal ; 7(314): ra19, 2014 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-24570487

RESUMO

Fasting glucose homeostasis is maintained in part through cAMP (adenosine 3',5'-monophosphate)-dependent transcriptional control of hepatic gluconeogenesis by the transcription factor CREB (cAMP response element-binding protein) and its coactivator CRTC2 (CREB-regulated transcriptional coactivator 2). We showed that PRMT6 (protein arginine methyltransferase 6) promotes fasting-induced transcriptional activation of the gluconeogenic program involving CRTC2. Mass spectrometric analysis indicated that PRMT6 associated with CRTC2. In cells, PRMT6 mediated asymmetric dimethylation of multiple arginine residues of CRTC2, which enhanced the association of CRTC2 with CREB on the promoters of gluconeogenic enzyme-encoding genes. In mice, ectopic expression of PRMT6 promoted higher blood glucose concentrations, which were associated with increased expression of genes encoding gluconeogenic factors, whereas knockdown of hepatic PRMT6 decreased fasting glycemia and improved pyruvate tolerance. The abundance of hepatic PRMT6 was increased in mouse models of obesity and insulin resistance, and adenovirus-mediated depletion of PRMT6 restored euglycemia in these mice. We propose that PRMT6 is involved in the regulation of hepatic glucose metabolism in a CRTC2-dependent manner.


Assuntos
Gluconeogênese , Glucose/metabolismo , Resistência à Insulina , Fígado/metabolismo , Obesidade/metabolismo , Fatores de Transcrição/metabolismo , Animais , Arginina/genética , Arginina/metabolismo , Linhagem Celular , AMP Cíclico/genética , AMP Cíclico/metabolismo , Glucose/genética , Humanos , Fígado/patologia , Metilação , Camundongos , Obesidade/genética , Obesidade/patologia , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Fatores de Transcrição/genética , Transcrição Genética
6.
Endocrinol Metab (Seoul) ; 29(4): 435-40, 2014 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-25559572

RESUMO

Glucose homeostasis is tightly controlled by the regulation of glucose production in the liver and glucose uptake into peripheral tissues, such as skeletal muscle and adipose tissue. Under prolonged fasting, hepatic gluconeogenesis is mainly responsible for glucose production in the liver, which is essential for tissues, organs, and cells, such as skeletal muscle, the brain, and red blood cells. Hepatic gluconeogenesis is controlled in part by the concerted actions of transcriptional regulators. Fasting signals are relayed by various intracellular enzymes, such as kinases, phosphatases, acetyltransferases, and deacetylases, which affect the transcriptional activity of transcription factors and transcriptional coactivators for gluconeogenic genes. Protein arginine methyltransferases (PRMTs) were recently added to the list of enzymes that are critical for regulating transcription in hepatic gluconeogenesis. In this review, we briefly discuss general aspects of PRMTs in the control of transcription. More specifically, we summarize the roles of four PRMTs: PRMT1, PRMT 4, PRMT 5, and PRMT 6, in the control of hepatic gluconeogenesis through specific regulation of FoxO1- and CREB-dependent transcriptional events.

7.
Int J Syst Evol Microbiol ; 61(Pt 11): 2654-8, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21148671

RESUMO

A Gram-reaction-negative, yellow-pigmented, gliding, rod-shaped, aerobic bacterium (RA5-111(T)) was isolated from foreshore soil. The taxonomic status of the novel isolate was determined using a polyphasic approach. On the basis of 16S rRNA gene sequence similarities, strain RA5-111(T) could be assigned to the genus Gramella, with sequence similarities of 97.7, 97.3 and 96.2 % to the type strains of Gramella echinicola, Gramella portivictoriae and Gramella marina, respectively. Chemotaxonomic and phenotypic characteristics also supported the affiliation of strain RA5-111(T) with the genus Gramella. The genomic DNA G+C content was 39.1 mol%. The isolate contained MK-6 as the predominant menaquinone, iso-C(15 : 0), iso-C(17 : 0) 3-OH and a summed feature (iso-C(15 : 0) 2-OH and/or C(16 : 1)ω7c) as major fatty acids, and phosphatidylethanolamine and unknown phospholipids as the polar lipids. DNA-DNA relatedness, phenotypic, genotypic and chemotaxonomic data clearly indicate that the isolate represents a novel species of the genus Gramella, for which the name Gramella gaetbulicola sp. nov. is proposed. The type strain is RA5-111(T) ( = KCTC 23022(T) = JCM 16528(T) = NBRC 106272(T)).


Assuntos
Flavobacteriaceae/classificação , Flavobacteriaceae/isolamento & purificação , Microbiologia do Solo , Composição de Bases , DNA Bacteriano/genética , Ácidos Graxos/metabolismo , Flavobacteriaceae/genética , Flavobacteriaceae/metabolismo , Dados de Sequência Molecular , Filogenia , RNA Ribossômico 16S/genética
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