The Role of Autophagy in Liver Epithelial Cells and Its Impact on Systemic Homeostasis

Tomaipitinca, Luana; Mandatori, Sara; Mancinelli, Romina; Giulitti, F.; Petrungaro, Simonetta; Moresi, Viviana; Facchiano, Antonio; Ziparo, Elio; Gaudio, Eugenio; Giampietri, Claudia

doi:10.3390/nu11040827

Cited by 22 publications

(14 citation statements)

References 128 publications

(144 reference statements)

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“…Macroautophagy (hereafter referred to as autophagy) is a highly conserved catabolic mechanism that ensures quality control of macromolecules and whole organelles. Autophagy contributes to cellular homoeostasis by regulating the turnover of cellular components and plays a pivotal role in the regulation of body metabolism [15,16]. Autophagy is involved in several biological processes, such as embryonic development and cellular differentiation, but also in stress-inducing responses, which enhance autophagy activation.…”

Section: Introductionmentioning

confidence: 99%

c-FLIP regulates autophagy by interacting with Beclin-1 and influencing its stability

et al. 2021

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Abstractc-FLIP (cellular FLICE-like inhibitory protein) protein is mostly known as an apoptosis modulator. However, increasing data underline that c-FLIP plays multiple roles in cellular homoeostasis, influencing differently the same pathways depending on its expression level and isoform predominance. Few and controversial data are available regarding c-FLIP function in autophagy. Here we show that autophagic flux is less effective in c-FLIP−/− than in WT MEFs (mouse embryonic fibroblasts). Indeed, we show that the absence of c-FLIP compromises the expression levels of pivotal factors in the generation of autophagosomes. In line with the role of c-FLIP as a scaffold protein, we found that c-FLIPL interacts with Beclin-1 (BECN1: coiled-coil, moesin-like BCL2-interacting protein), which is required for autophagosome nucleation. By a combination of bioinformatics tools and biochemistry assays, we demonstrate that c-FLIPL interaction with Beclin-1 is important to prevent Beclin-1 ubiquitination and degradation through the proteasomal pathway. Taken together, our data describe a novel molecular mechanism through which c-FLIPL positively regulates autophagy, by enhancing Beclin-1 protein stability.

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Section: Introductionmentioning

confidence: 99%

c-FLIP regulates autophagy by interacting with Beclin-1 and influencing its stability

et al. 2021

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“…Autophagy, a self-protecting cellular catabolic process appointed to the recycling of biomolecules, is interestingly one of the molecular processes involved in the pathology of atherosclerosis (19,20). So far, three forms of autophagy have been described: macroautophagy, microautophagy, and chaperone-mediated autophagy; hereafter, we refer to macroautophagy as autophagy (21,22). In early atherosclerotic plaques, autophagy preserves normal cellular function to protect cells against oxidative injury, metabolic stress, and inflammation (23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

Altered Tregs Differentiation and Impaired Autophagy Correlate to Atherosclerotic Disease

et al. 2020

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Atherosclerosis is a progressive vascular disease representing the primary cause of morbidity and mortality in developed countries. Formerly, atherosclerosis was considered as a mere passive accumulation of lipids in blood vessels. However, it is now clear that atherosclerosis is a complex and multifactorial disease, in which the involvement of immune cells and inflammation play a key role. A variety of studies have shown that autophagy-a cellular catalytic mechanism able to remove injured cytoplasmic components in response to cellular stress-may be proatherogenic. So far, in this context, its role has been investigated in smooth muscle cells, macrophages, and endothelial cells, while the function of this catabolic protective process in lymphocyte functionality has been overlooked. The few studies carried out so far, however, suggested that autophagy modulation in lymphocyte subsets may be functionally related to plaque formation and development. Therefore, in this research, we aimed at better clarifying the role of lymphocyte subsets, mainly regulatory T cells (Tregs), in human atherosclerotic plaques and in animal models of atherosclerosis investigating the contribution of autophagy on immune cell homeostasis. Here, we investigate basal autophagy in a mouse model of atherosclerosis, apolipoprotein E (ApoE)-knockout (KO) mice, and we analyze the role of autophagy in driving Tregs polarization. We observed defective maturation of Tregs from ApoE-KO mice in response to tumor growth factor-β (TGFβ). TGFβ is a well-known autophagy inducer, and Tregs maturation defects in ApoE-KO mice seem to be related to autophagy impairment. In this work, we propose that autophagy underlies Tregs maturation, advocating that the study of this process in atherosclerosis may open new therapeutic strategies.

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“…Chaperonemediated autophagy involves the recognition of substrates (mainly abnormal or damaged proteins) with a KFERQ motif, whereas microautophagy involves direct sequestration of cytoplasmic portions into the lysosome. Modified according to [268]. 5 Oxidative Medicine and Cellular Longevity (microtubule-associated-protein-light-chain-3)-PE (phosphatidylethanolamine) formation analogous to E3 enzymes during ubiquitin conjugation reactions.…”

Section: Endoplasmic Reticulum-associated Protein Degradation (Erad)mentioning

confidence: 99%

Proteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress

Höhn

Tramutola

Cascella

2020

Oxidative Medicine and Cellular Longevity

127

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Protein homeostasis or proteostasis is an essential balance of cellular protein levels mediated through an extensive network of biochemical pathways that regulate different steps of the protein quality control, from the synthesis to the degradation. All proteins in a cell continuously turn over, contributing to development, differentiation, and aging. Due to the multiple interactions and connections of proteostasis pathways, exposure to stress conditions may cause various types of protein damage, altering cellular homeostasis and disrupting the entire network with additional cellular stress. Furthermore, protein misfolding and/or alterations during protein synthesis results in inactive or toxic proteins, which may overload the degradation mechanisms. The maintenance of a balanced proteome, preventing the formation of impaired proteins, is accomplished by two major catabolic routes: the ubiquitin proteasomal system (UPS) and the autophagy-lysosomal system. The proteostasis network is particularly important in nondividing, long-lived cells, such as neurons, as its failure is implicated with the development of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. These neurological disorders share common risk factors such as aging, oxidative stress, environmental stress, and protein dysfunction, all of which alter cellular proteostasis, suggesting that general mechanisms controlling proteostasis may underlay the etiology of these diseases. In this review, we describe the major pathways of cellular proteostasis and discuss how their disruption contributes to the onset and progression of neurodegenerative diseases, focusing on the role of oxidative stress.

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The Role of Autophagy in Liver Epithelial Cells and Its Impact on Systemic Homeostasis

Cited by 22 publications

References 128 publications

c-FLIP regulates autophagy by interacting with Beclin-1 and influencing its stability

c-FLIP regulates autophagy by interacting with Beclin-1 and influencing its stability

Altered Tregs Differentiation and Impaired Autophagy Correlate to Atherosclerotic Disease

Proteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress

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