Activating transcription factor 3 in immune response and metabolic regulation

Jadhav, Kavita; Zhang, Yanqiao

doi:10.1016/j.livres.2017.08.001

Cited by 57 publications

(50 citation statements)

References 58 publications

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“…Previous studies focusing on the role of ATF3 in hepatic steatosis, glucose, and insulin homeostasis came out with contradictory conclusions . Recently, a study published by Kim et al corroborated the fact that ATF3 is the key molecule linking hepatic steatosis and impaired glucose homeostasis .…”

Section: Discussionmentioning

confidence: 99%

Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3

Fang

Zhang

et al. 2020

Hepatology

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Background and Aims Although knowledge regarding the pathogenesis of nonalcoholic fatty liver disease (NAFLD) has profoundly grown in recent decades, the internal restrictive mechanisms remain largely unknown. We have recently reported that the transcription repressor interferon regulatory factor‐2 binding protein 2 (IRF2BP2) is enriched in cardiomyocytes and inhibits pathological cardiac hypertrophy in mice. Notably, IRF2BP2 is abundantly expressed in hepatocytes and dramatically down‐regulated in steatotic livers, whereas the role of IRF2BP2 in NAFLD is unknown. Approach and Results Herein, using gain‐of‐function and loss‐of‐function approaches in mice, we demonstrated that while hepatocyte‐specific Irf2bp2 knockout exacerbated high‐fat diet–induced hepatic steatosis, insulin resistance and inflammation, hepatic Irf2bp2 overexpression protected mice from these metabolic disorders. Moreover, the inhibitory role of IRF2BP2 on hepatosteatosis is conserved in a human hepatic cell line in vitro. Combinational analysis of digital gene expression and chromatin immunoprecipitation sequencing identified activating transcription factor 3 (ATF3) to be negatively regulated by IRF2BP2 in NAFLD. Chromatin immunoprecipitation and luciferase assay substantiated the fact that IRF2BP2 is a bona fide transcription repressor of ATF3 gene expression via binding to its promoter region. Functional studies revealed that ATF3 knockdown significantly relieved IRF2BP2 knockout‐exaggerated hepatosteatosis in vitro. Conclusion IRF2BP2 is an integrative restrainer in controlling hepatic steatosis, insulin resistance, and inflammation in NAFLD through transcriptionally repressing ATF3 gene expression.

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Section: Discussionmentioning

confidence: 99%

Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3

Fang

Zhang

et al. 2020

Hepatology

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“…has been shown that ATF3 is rapidly induced by a wide range of challenges such as DNA damage, oxidative and ER stress (9,10), leading to the activation of signaling pathways required for the maintenance of cellular homeostasis (8,11). ATF3 is known to activate and repress transcription through its binding to the canonical cis-regulatory element 5'-TGACGTCA-3' via its basic region-leucine zipper domain as an homodimer or heterodimer, in combination with other ATFs or AP-1 transcription factors (12). Despite the evidence linking ATF3 to cellular stressors, there is currently no data on whether ATF3 levels are regulated by stimuli such as cold or -adrenergic signaling in adipose depots.…”

Section: Introductionmentioning

confidence: 99%

The mRNA levels of heat shock factor 1 are regulated by thermogenic signals via the cAMP-dependent transcription factor ATF3

Verma¹,

Périè²,

Mueller

2020

Journal of Biological Chemistry

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Heat shock factor 1 (HSF1) regulates cellular adaptation to challenges such as heat shock and oxidative and proteotoxic stresses. We have recently reported a previously unappreciated role for HSF1 in the regulation of energy metabolism in fat tissues; however, whether HSF1 is differentially expressed in adipose depots and how its levels are regulated in fat tissues remain unclear. Here, we show that HSF1 levels are higher in brown and subcutaneous fat tissues than in those in the visceral depot and that HSF1 is more abundant in differentiated, thermogenic adipocytes. Gene expression experiments indicated that HSF1 is transcriptionally regulated in fat by agents that modulate cAMP levels, by cold exposure, and by pharmacological stimulation of β-adrenergic signaling. An in silico promoter analysis helped identify a putative response element for activating transcription factor 3 (ATF3) at −258 to −250 base pairs from the HSF1 transcriptional start site, and electrophoretic mobility shift and ChIP assays confirmed ATF3 binding to this sequence. Furthermore, functional assays disclosed that ATF3 is necessary and sufficient for HSF1 regulation. Detailed gene expression analysis revealed that ATF3 is one of the most highly induced ATFs in thermogenic tissues of mice exposed to cold temperatures or treated with the β-adrenergic receptor agonist CL316,243 and that its expression is induced by modulators of cAMP levels in isolated adipocytes. To the best of our knowledge, our results show for the first time that HSF1 is transcriptionally controlled by ATF3 in response to classic stimuli that promote heat generation in thermogenic tissues.

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“…For instance, the translocases of the outer mitochondrial membrane (OMM), TOMM22 and TOMM70, were differentially phosphorylated at multiple sites which is thought to regulate mitochondrial protein import (Matic et al, 2018;Schmidt et al, 2011). The down-modulation of ATF3 is a bZIP domain transcription factor implicated in multiple cellular stress responses that can either activate or repress transcription of its target genes (Jadhav and Zhang, 2017). Interestingly, ATF3 has been recently discussed as one of the putative mammalian homologues of ATFS-1, the central UPR mt regulator in C.elegans (Münch and Harper, 2016).…”

Section: Lp Reshapes the Mitochondrial Proteomementioning

confidence: 99%

Dynamic proteomics profiling ofLegionella pneumophilainfection unveils modulation of the host mitochondrial stress response pathway

Noack

Jimenez-Morales

Stevenson

et al. 2020

Preprint

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The human pathogen Legionella pneumophila (L.p.) secretes ~330 bacterial effector proteins into the host cell which interfere with numerous cellular pathways and often regulate host cell proteins through post-translational modifications. However, the cellular targets and functions of most L.p. effectors are not known. In order to obtain a global overview of potential targets of these effectors, we analyzed the host cell proteome, ubiquitinome, and phosphoproteome during L.p. infection. Our analysis reveals dramatic spatiotemporal changes in the host cell proteome that are dependent on the secretion of bacterial effectors. Strikingly, we show that L.p. substantially reshapes the mitochondrial proteome and modulates mitochondrial stress response pathways such as the mitochondrial unfolded protein response (UPR mt ). To our knowledge, this is the first evidence of manipulation of the UPR mt by a bacterial pathogen in mammalian cells. In addition, we have identified a previously uncharacterized L.p. effector that is targeted to host cell mitochondria and protects mitochondrial network integrity during mitochondrial stress.

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Activating transcription factor 3 in immune response and metabolic regulation

Cited by 57 publications

References 58 publications

Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3

Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3

The mRNA levels of heat shock factor 1 are regulated by thermogenic signals via the cAMP-dependent transcription factor ATF3

Dynamic proteomics profiling ofLegionella pneumophilainfection unveils modulation of the host mitochondrial stress response pathway

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