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TFEB insufficiency promotes cardiac hypertrophy by blocking autophagic degradation of GATA4.

ABSTRACT: Autophagosome-lysosome pathway (ALP) insufficiency has been suggested to play a critical role in the pathogenesis of cardiac hypertrophy. However, the mechanisms underlying ALP insufficiency remain largely unknown, and strategies to specifically manipulate ALP insufficiency for treating cardiac hypertrophy are lacking. Transcription factor EB (TFEB), as a master regulator of ALP, regulates the generation and function of autophagosomes and lysosomes. We found that TFEB was significantly decreased, whereas autophagosome markers were increased in phenylephrine (PE)-induced and transverse aortic constriction-induced cardiomyocyte hypertrophy and failing hearts from patients with dilated cardiomyopathy. Knocking down TFEB induced ALP insufficiency, as indicated by increased autophagosome markers, decreased light chain 3II flux, and cardiomyocyte hypertrophy manifested through increased levels of atrial natriuretic peptide and β-myosin heavy chain and enlarged cell size. The effects of TFEB knockdown were abolished by promoting autophagy. TFEB overexpression improved autophagic flux and attenuated PE-stimulated cardiomyocyte hypertrophy and transverse aortic constriction-induced hypertrophic remodeling, fibrosis, and cardiac dysfunction. Curcumin analog compound C1, a specific TFEB activator, similarly attenuated PE-induced ALP insufficiency and cardiomyocyte hypertrophy. TFEB knockdown increased the accumulation of GATA4, a transcription factor for several genes causing cardiac hypertrophy by blocking autophagic degradation of GATA4, whereas knocking down GATA4 attenuated TFEB downregulation-induced cardiomyocyte hypertrophy. Both TFEB overexpression and C1 promoted GATA4 autophagic degradation and alleviated PE-induced cardiomyocyte hypertrophy. In conclusion, TFEB downregulation plays a vital role in the development of pressure overload-induced cardiac hypertrophy by causing ALP insufficiency and blocking autophagic degradation. Activation of TFEB represents a potential therapeutic strategy for treating cardiac hypertrophy.

SUBMITTER: Song R

PROVIDER: S-EPMC8498468 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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TFEB insufficiency promotes cardiac hypertrophy by blocking autophagic degradation of GATA4.

Song Rui R Lei Han H Feng Li L Cheng Wanwen W Li Ying Y Yao Ling Ling LL Liu Jie J

The Journal of biological chemistry 20210910 4

Autophagosome-lysosome pathway (ALP) insufficiency has been suggested to play a critical role in the pathogenesis of cardiac hypertrophy. However, the mechanisms underlying ALP insufficiency remain largely unknown, and strategies to specifically manipulate ALP insufficiency for treating cardiac hypertrophy are lacking. Transcription factor EB (TFEB), as a master regulator of ALP, regulates the generation and function of autophagosomes and lysosomes. We found that TFEB was significantly decreased ...[more]

PMID: 34517007

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Project description:AimsSenescence-associated pathological cardiac hypertrophy (SA-PCH) is associated with upregulation of foetal genes, fibrosis, senescence-associated secretory phenotype (SASP), cardiac dysfunction and increased morbidity and mortality. Therefore, we conducted experiments to investigate whether GATA4 accumulation induces SA-PCH, and whether Bmi-1-RING1B promotes GATA4 ubiquitination and its selective autophagic degradation to prevent SA-PCH.Methods and resultsBmi-1-deficient (Bmi-1-/- ), transgenic Bmi-1 overexpressing (Bmi-1Tg ) and wild-type (WT) mice were infused with angiotensin II (Ang II) to stimulate the development of SA-PCH. Through bioinformatics analysis with RNA sequencing data from cardiac tissues, we found that Bmi-1-RING1B and autophagy are negatively related to SA-PCH. Bmi-1 deficiency promoted GATA4-dependent SA-PCH by increasing GATA4 protein and hypertrophy-related molecules transcribed by GATA4 such as ANP and BNP. Bmi-1 deficiency stimulated NF-κB-p65-dependent SASP, leading to cardiac dysfunction, cardiomyocyte hypertrophy and senescence. Bmi-1 overexpression repressed GATA4-dependent SA-PCH. GATA4 degraded by Bmi-1 was mainly dependent on autophagy rather than proteasome. In human myocardium, p16 positively correlated with ANP and GATA4 and negatively correlated with LC3B, Bmi-1 and RING1B; GATA4 positively correlated with p62 and negatively correlated with Bmi-1 and LC3B. With increased p16 protein levels, ANP-, BNP- and GATA4-positive cells or areas increased; however, LC3B-positive cells or areas decreased in human myocardium. GATA4 is ubiquitinated after combining with Bmi-1-RING1B, which is then recognised by p62, is translocated to autophagosomes to form autophagolysosomes and degraded. Downregulated GATA4 ameliorated SA-PCH and cardiac dysfunction by reducing GATA4-dependent hypertrophy and SASP-related molecules. Bmi-1 combined with RING1B (residues 1-179) and C-terminus of GATA4 (residues 206-443 including zinc finger domains) through residues 1-95, including a RING-HC-finger. RING1B combined with C-terminus of GATA4 through the C-terminus (residues 180-336). Adeno-associated viral vector serotype 9 (AAV9)-cytomegalovirus (CMV)-Bmi-1-RING1B treatment significantly attenuated GATA4-dependent SA-PCH through promoting GATA4 autophagic degradation.ConclusionsBmi-1-RING1B maintained cardiac function and prevented SA-PCH by promoting selective autophagy for degrading GATA4.Translational perspectiveAAV9-CMV-Bmi-1-RING1B could be used for translational gene therapy to ubiquitinate GATA4 and prevent GATA4-dependent SA-PCH. Also, the combined domains between Bmi-1-RING1B and GATA4 in aging cardiomyocytes could be therapeutic targets for identifying stapled peptides in clinical applications to promote the combination of Bmi-1-RING1B with GATA4 and the ubiquitination of GATA4 to prevent SA-PCH and heart failure. We found that degradation of cardiac GATA4 by Bmi-1 was mainly dependent on autophagy rather than proteasome, and autophagy agonists metformin and rapamycin could ameliorate the SA-PCH, suggesting that activation of autophagy with metformin or rapamycin could also be a promising method to prevent SA-PCH.

Project description:Hepatitis B virus (HBV) particles are thought to be secreted from hepatocytes through multivesicular bodies (MVBs); however, the cellular trafficking mechanisms prior to this process remain elusive. It has been reported that CCDC88A/GIV expression, which is involved in multiple aspects of vesicular trafficking, changes dynamically at different phases of chronic HBV infection. In this study, we focused on the role of CCDC88A/GIV in HBV replication. In the liver tissues of chronically HBV-infected patients, HBV infection significantly enhanced CCDC88A/GIV expression, and increased endoplasmic reticulum (ER) stress and autophagosome formation without changing endosome formation. Additionally, colocalization of SHBsAg with early endosomes (~30.2%) far exceeded that with autophagosomes (~3.2%). In hepatoma cells, CCDC88A/GIV and its downstream proteins, DNM2 (dynamin 2; a CCDC88A/GIV effector), CLTC and RAB5A significantly enhanced HBV replication and endosome formation but inhibited autophagosome formation. Blocking endocytosis disrupted HBsAg trafficking to endosomes and caused its accumulation in the ER lumen, which triggered ER stress to initiate the unfolded protein response (UPR). Therefore, HBsAg trafficking into autophagosomes was increased, and the lysosomal activity and maturation, which was inhibited by HBV infection, were restored. Meanwhile, core particles were prevented from entering MVBs. CCDC88A/GIV and its other effector, GNAI3, decreased autophagic flux by enhancing the insulin-induced AKT-MTOR pathway, thereby inhibiting HBV antigens autophagic degradation. In conclusion, CCDC88A/GIV enhanced HBV replication by increasing endosomal trafficking and reducing autophagic degradation of HBV antigens, suggesting that CCDC88A/GIV-mediated endosomal trafficking plays an important role in HBV replication and progeny secretion.Abbreviations: ACTB: actin beta; AO: acridine orange; ATF6: activating transcription factor 6; CCDC88A/GIV: coiled-coil domain containing 88A; CLTC: clathrin heavy chain; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DNM2: dynamin 2; ER: endoplasmic reticulum; ERN1: endoplasmic reticulum to nucleus signaling 1; EIF2A: eukaryotic translation initiation factor 2A; FBS: fetal bovine serum; GNAI3: G protein subunit alpha i3; HBV: hepatitis B virus; HBV RIs: HBV replication intermediates; HBcAg: HBV core protein; HBsAg: HBV surface antigen; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MVBs: multivesicular bodies; MTOR: mechanistic target of rapamycin kinase; PDI: protein disulfide isomerase; PHH: primary human hepatocyte; pSM2: a HBV replication-competent plasmid; HSPA5/BIP: heat shock protein family A (Hsp70) member 5; SQSTM1/p62: sequestosome 1; siRNA: small interfering RNA; SEM: standard error of the mean; UPR: unfolded protein response.

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TFEB insufficiency promotes cardiac hypertrophy by blocking autophagic degradation of GATA4.

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TFEB insufficiency promotes cardiac hypertrophy by blocking autophagic degradation of GATA4.

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