Jun Proteins Are Starvation-Regulated Inhibitors of Autophagy

Yogev, Orli; Goldberg, Rachel; Anzi, Shira; Yogev, Ohad; Shaulian, Eitan

doi:10.1158/0008-5472.can-09-3408

Cited by 44 publications

(31 citation statements)

References 44 publications

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“…tors of the autophagic process (12)(13)(14)41). We provide evidence that the TCR/CD28-stimulated signaling pathways that regulate the induction of autophagy gene expression involve both the Rasmitogen-activated protein kinase and JNK signaling cascades.…”

Section: Discussionmentioning

confidence: 93%

Epigenetic Regulation of Autophagy by the Methyltransferase G9a

Narvajas

Gomez

Zhang

et al. 2013

Molecular and Cellular Biology

182

163

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Macroautophagy is an evolutionarily conserved cellular process involved in the clearance of proteins and organelles. Although the cytoplasmic machinery that orchestrates autophagy induction during starvation, hypoxia, or receptor stimulation has been widely studied, the key epigenetic events that initiate and maintain the autophagy process remain unknown. Here we show that the methyltransferase G9a coordinates the transcriptional activation of key regulators of autophagosome formation by remodeling the chromatin landscape. Pharmacological inhibition or RNA interference (RNAi)-mediated suppression of G9a induces LC3B expression and lipidation that is dependent on RNA synthesis, protein translation, and the methyltransferase activity of G9a. Under normal conditions, G9a associates with the LC3B, WIPI1, and DOR gene promoters, epigenetically repressing them. However, G9a and G9a-repressive histone marks are removed during starvation and receptor-stimulated activation of naive T cells, two physiological inducers of macroautophagy. Moreover, we show that the c-Jun N-terminal kinase (JNK) pathway is involved in the regulation of autophagy gene expression during naive-T-cell activation. Together, these findings reveal that G9a directly represses genes known to participate in the autophagic process and that inhibition of G9a-mediated epigenetic repression represents an important regulatory mechanism during autophagy.A utophagy is an evolutionarily conserved catabolic process in eukaryotes that involves lysosomal degradation of cellular components, including long-lived proteins and organelles. There are four main forms of autophagy: macroautophagy (referred to here as autophagy), selective autophagy, microautophagy, and chaperone-mediated autophagy (1-4). Autophagy serves as an adaptive response to protect cells or organisms during periods of cellular stress, such as nutrient deprivation. In addition, autophagy can participate in several cellular and developmental processes, including homeostasis, clearance of intracellular pathogens, and immunity (1). Due to its fundamental importance for cellular survival, autophagy regulation has been implicated in several human diseases, such as cancer and neurodegenerative disorders (2, 5).Autophagy initiation involves the de novo synthesis of a double-membrane structure known as the phagophore, which ultimately elongates and closes to sequester cytoplasmic proteins and organelles, forming the autophagosome. The autophagosome subsequently undergoes a stepwise maturation process that culminates in its fusion with acidified endosomal/lysosomal vesicles, resulting in the degradation of its contents into useful biomolecules (2). A screen of yeast mutants unable to survive under nitrogen deprivation characterized a network of autophagy-related (ATG) genes (6). Mammalian homologues of these ATGs were later identified and shown to participate during distinct steps of autophagy. For example, microtubule-associated protein light chain 3 (LC3B) undergoes lipidation and is recruited to the pha...

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Section: Discussionmentioning

confidence: 93%

Epigenetic Regulation of Autophagy by the Methyltransferase G9a

Narvajas

Gomez

Zhang

et al. 2013

Molecular and Cellular Biology

182

163

View full text Add to dashboard Cite

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“…It has been reported that rapamycin inhibits phytohemagglutinin-induced c-Jun expression in human T cells (30), and that starvation, which inhibits mTOR activity, also reduces c-Jun expression (31). However, the underlying mechanism has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

Restoration of Corticosteroid Sensitivity in Chronic Obstructive Pulmonary Disease by Inhibition of Mammalian Target of Rapamycin

Mitani

Ito

Vuppusetty

et al. 2016

Am J Respir Crit Care Med

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Rationale: Corticosteroid resistance is a major barrier to the effective treatment of chronic obstructive pulmonary disease (COPD). Several molecular mechanisms have been proposed, such as activations of the phosphoinositide-3-kinase/Akt pathway and p38 mitogen-activated protein kinase. However, the mechanism for corticosteroid resistance is still not fully elucidated.Objectives: To investigate the role of mammalian target of rapamycin (mTOR) in corticosteroid sensitivity in COPD.Methods: The corticosteroid sensitivity of peripheral blood mononuclear cells collected from patients with COPD, smokers, and nonsmoking control subjects, or of human monocytic U937 cells exposed to cigarette smoke extract (CSE), was quantified as the dexamethasone concentration required to achieve 30% inhibition of tumor necrosis factor-a-induced CXCL8 production in the presence or absence of the mTOR inhibitor rapamycin. mTOR activity was determined as the phosphorylation of p70 S6 kinase, using Western blotting.Measurements and Main Results: mTOR activity was increased in peripheral blood mononuclear cells from patients with COPD, and treatment with rapamycin inhibited this as well as restoring corticosteroid sensitivity. In U937 cells, CSE stimulated mTOR activity and c-Jun expression, but pretreatment with rapamycin inhibited both and also reversed CSE-induced corticosteroid insensitivity.Conclusions: mTOR inhibition by rapamycin restores corticosteroid sensitivity via inhibition of c-Jun expression, and thus mTOR is a potential novel therapeutic target for COPD.

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“…JunB inhibition of autophagy is independent of mTOR activation. 37 JunB and c-Jun inhibition of starvation-induced autophagy are dependent on both the dimerization domain and the DNA binding domain, implicating a requirement of their transcription regulation activities for their inhibition of autophagy. Here we found that GABARAPL1, SQSTM1, SLC11A1 ABCA2, WDFY3, CAPN6, CAPN12, MAPK3 and PPP1R15A, may be regulated by AP-1, thus providing transcriptional inhibition of autophagy.…”

confidence: 99%

“…37 Starvation induces transient induction of JunB and c-Jun and downregulation of their mRNA and proteins after one hour. Overexpression of JunB inhibits autophagy induced by starvation, as assessed by both LC3-GFP puncta accumulation and by p62 clearance.…”

confidence: 99%