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Autophagy is an evolutionarily conserved process that promotes the lysosomal degradation of intracellular components including organelles and portions of the cytoplasm. Besides operating as a quality control mechanism in steady-state conditions, autophagy is upregulated in response to a variety of homeostatic perturbations. In this setting, autophagy mediates prominent cytoprotective effects as it sustains energetic homeostasis and contributes to the removal of cytotoxic stimuli, thus orchestrating a cell-wide, multipronged adaptive response to stress. In line with the critical role of autophagy in health and disease, defects in the autophagic machinery as well as in autophagy-regulatory signaling pathways have been associated with multiple human pathologies, including neurodegenerative disorders, autoimmune conditions and cancer. Accumulating evidence indicates that the autophagic response to stress may proceed in two phases. Thus, a rapid increase in the autophagic flux, which occurs within minutes or hours of exposure to stressful conditions and is entirely mediated by post-translational protein modifications, is generally followed by a delayed and protracted autophagic response that relies on the activation of specific transcriptional programs. Stress-responsive transcription factors including p53, NF-κB and STAT3 have recently been shown to play a major role in the regulation of both these phases of the autophagic response. Here, we will discuss the molecular mechanisms whereby autophagy is orchestrated by stress-responsive transcription factors., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Amyloidoses are characterized by the accumulation and aggregation of misfolded proteins into fibrils in different organs, leading to cell death and consequent organ dysfunction. The specific substitution of Leu 75 for Pro in Apolipoprotein A-I protein sequence (ApoA-I; L75P-ApoA-I) results in late onset amyloidosis, where deposition of extracellular protein aggregates damages the normal functions of the liver. In this work, we describe that the autophagic process is inhibited in the presence of the L75P-ApoA-I amyloidogenic variant in stably transfected human hepatocyte carcinoma cells. The L75P-ApoA-I amyloidogenic variant alters the redox status of the cells, resulting into excessive mitochondrial stress and consequent cell death. Moreover, L75P-ApoA-I induces an impairment of the autophagic flux. Pharmacological induction of autophagy or transfection-enforced overexpression of the pro-autophagic transcription factor EB (TFEB) restores proficient proteostasis and reduces oxidative stress in these experimental settings, suggesting that pharmacological stimulation of autophagy could be a promising target to alleviate ApoA-I amyloidosis. [ABSTRACT FROM AUTHOR]

Autophagy is an evolutionarily conserved catabolic pathway that is involved in numerous physiological processes and in multiple pathological conditions including cancer. Autophagy is regulated by an intricate network of signaling cascades that have not yet been entirely disentangled. Accumulating evidence indicates that p53, the best-characterized human tumor suppressor protein, can modulate autophagy in a dual fashion, depending on its subcellular localization. On the one hand, p53 functions as a nuclear transcription factor and transactivates proapoptotic, cell cycle-arresting and proautophagic genes. On the other hand, cytoplasmic p53 can operate at mitochondria to promote cell death and can repress autophagy via poorly characterized mechanisms. This review focuses on the recently discovered function of p53 as a master regulator of autophagy. [Copyright &y& Elsevier]

In response to stress, cells start transcriptional and transcription-independent programs that can lead to adaptation or death. Here, we show that multiple inducers of autophagy, including nutrient depletion, trigger the activation of the IKK (IκB kinase) complex that is best known for its essential role in the activation of the transcription factor NF-κB by stress. Constitutively active IKK subunits stimulated autophagy and transduced multiple signals that operate in starvation-induced autophagy, including the phosphorylation of AMPK and JNK1. Genetic inhibition of the nuclear translocation of NF-κB or ablation of the p65/RelA NF-κB subunit failed to suppress IKK-induced autophagy, indicating that IKK can promote the autophagic pathway in an NF-κB-independent manner. In murine and human cells, knockout and/or knockdown of IKK subunits (but not that of p65) prevented the induction of autophagy in response to multiple stimuli. Moreover, the knockout of IKK-β suppressed the activation of autophagy by food deprivation or rapamycin injections in vivo, in mice. Altogether, these results indicate that IKK has a cardinal role in the stimulation of autophagy by physiological and pharmacological stimuli. [ABSTRACT FROM AUTHOR]

Abstract: Oxidative stress plays an important role in inflammatory process of celiac disease. We have studied the effect of the lycopene, quercetin and tyrosol natural antioxidants on the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) gene expression in RAW 264.7 macrophages stimulated by gliadin in association with IFN-γ. The IFN-γ plus gliadin combination treatment was capable of enhancing iNOS and COX-2 gene expression and nuclear factor-κB (NF-κB), interferon regulatory factor-1 (IRF-1) and signal transducer and activator of transcription-1α (STAT-1α) activation induced by reactive oxygen species generation at 24 h. Lycopene, quercetin and tyrosol inhibited all these effects. The results here reported suggest that these compounds may represent non toxic agents for the control of pro-inflammatory genes involved in celiac disease. [Copyright &y& Elsevier]

NF-κB regulates inflammatory and immune response by increasing the expression of specific genes. In celiac disease proinflammatory cytokines, adhesion molecules, and enzymes whose gene expression is known to be regulated by NF-κB are involved. This study investigated the activation of NF-κB in inflamed mucosa from patients with untreated celiac disease. Biopsy specimens from control, untreated, and treated patients were subjected to molecular biology analysis. NF-κB activation was evaluated by electrophoretic mobility shift assay. NF-κB related subunit protein level, and inducible nitric oxide synthase and cyclo-oxygenase 2 protein expression was analyzed by western blot. Both NF-κB/DNA binding activity and p50/p65 nuclear levels were higher in biopsy specimens from untreated patients than in those from treated patients and controls. The degradation of IκBβ in the cytosol and the reappearance in the nucleus indicated a persistent NF-κB activation in celiac disease. NF-κB activity was maintained in cultured biopsy specimens up to 6 h and decreased at 24 h, and then the addition of peptic-tryptic digest of gliadin caused the recovery of NF-κB activity at 6 h. NF-κB/DNA binding activity was correlated with inducible nitric oxide synthase and cyclo-oxygenase-2 protein expression. These results show for the first time that NF-κB is activated in the inflamed mucosa of celiac patients and suggest that it may represent a molecular target for the modulation of inflammatory response in celiac disease. [ABSTRACT FROM AUTHOR]