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3 pages, 195 KiB

Open AccessEditorial

Editorial: Highlights in Autophagy—From Basic Mechanisms to Human Disorder Treatments

by Pei-Hui Lin and Lydie Combaret

Cells 2023, 12(1), 188; https://doi.org/10.3390/cells12010188 - 03 Jan 2023

Cited by 2 | Viewed by 1455

Abstract

Autophagy is an evolutionarily conserved catabolic process and represents a field of research that is constantly growing [...] Full article

(This article belongs to the Special Issue Highlights in Autophagy: From Basic Mechanisms to Human Disorder Treatments)

Research

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16 pages, 3076 KiB

Open AccessArticle

PFKFB3 Inhibition Impairs Erlotinib-Induced Autophagy in NSCLCs

by Nadiia Lypova, Susan M. Dougherty, Lilibeth Lanceta, Jason Chesney and Yoannis Imbert-Fernandez

Cells 2021, 10(7), 1679; https://doi.org/10.3390/cells10071679 - 03 Jul 2021

Cited by 11 | Viewed by 2557

Abstract

Tyrosine kinase inhibitors (TKIs) targeting the kinase domain of the epidermal growth factor receptor (EGFR), such as erlotinib, have dramatically improved clinical outcomes of patients with EGFR-driven non-small cell lung carcinomas (NSCLCs). However, intrinsic or acquired resistance remains a clinical barrier to the [...] Read more.

Tyrosine kinase inhibitors (TKIs) targeting the kinase domain of the epidermal growth factor receptor (EGFR), such as erlotinib, have dramatically improved clinical outcomes of patients with EGFR-driven non-small cell lung carcinomas (NSCLCs). However, intrinsic or acquired resistance remains a clinical barrier to the success of FDA-approved EGFR TKIs. Multiple mechanisms of resistance have been identified, including the activation of prosurvival autophagy. We have previously shown that the expression and activity of PFKFB3—a known driver of glycolysis—is associated with resistance to erlotinib and that PFKFB3 inhibition improves the response of NSCLC cells to erlotinib. This study focuses on investigating the role of PFKFB3 in regulating erlotinib-driven autophagy to escape resistance to erlotinib. We evaluated the consequence of pharmacological inhibition of PFKFB3 on erlotinib-driven autophagy in NSCLC cells with different mutation statuses. Here, we identify PFKFB3 as a mediator of erlotinib-induced autophagy in NSCLCs. We demonstrate that PFKFB3 inhibition sensitizes NCSLCs to erlotinib via impairing autophagy flux. In summary, our studies uncovered a novel crosstalk between PFKFB3 and EGFR that regulates erlotinib-induced autophagy, thus contributing to erlotinib sensitivity in NSCLCs. Full article

(This article belongs to the Special Issue Highlights in Autophagy: From Basic Mechanisms to Human Disorder Treatments)

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15 pages, 2271 KiB

Open AccessArticle

Integrated Action of Autophagy and Adipose Tissue Triglyceride Lipase Ameliorates Diet-Induced Hepatic Steatosis in Liver-Specific PLIN2 Knockout Mice

by John D. Griffin, Eloy Bejarano, Xiang-Dong Wang and Andrew S. Greenberg

Cells 2021, 10(5), 1016; https://doi.org/10.3390/cells10051016 - 25 Apr 2021

Cited by 18 | Viewed by 3942

Abstract

An imbalance in the storage and breakdown of hepatic lipid droplet (LD) triglyceride (TAG) leads to hepatic steatosis, a defining feature of non-alcoholic fatty liver disease (NAFLD). The two primary cellular pathways regulating hepatic TAG catabolism are lipolysis, initiated by adipose triglyceride lipase [...] Read more.

An imbalance in the storage and breakdown of hepatic lipid droplet (LD) triglyceride (TAG) leads to hepatic steatosis, a defining feature of non-alcoholic fatty liver disease (NAFLD). The two primary cellular pathways regulating hepatic TAG catabolism are lipolysis, initiated by adipose triglyceride lipase (ATGL), and lipophagy. Each of these processes requires access to the LD surface to initiate LD TAG catabolism. Ablation of perilipin 2 (PLIN2), the most abundant lipid droplet-associated protein in steatotic liver, protects mice from diet-induced NAFLD. However, the mechanisms underlaying this protection are unclear. We tested the contributions of ATGL and lipophagy mediated lipolysis to reduced hepatic TAG in mice with liver-specific PLIN2 deficiency (PLIN2^LKO) fed a Western-type diet for 12 weeks. We observed enhanced autophagy in the absence of PLIN2, as determined by ex vivo p62 flux, as well as increased p62- and LC3-positive autophagic vesicles in PLIN2^LKO livers and isolated primary hepatocytes. Increased levels of autophagy correlated with significant increases in cellular fatty acid (FA) oxidation in PLIN2^LKO hepatocytes. We observed that inhibition of either autophagy or ATGL blunted the increased FA oxidation in PLIN2^LKO hepatocytes. Additionally, combined inhibition of ATGL and autophagy reduced FA oxidation to the same extent as treatment with either inhibitor alone. In sum, these studies show that protection against NAFLD in the absence of hepatic PLIN2 is driven by the integrated actions of both ATGL and lipophagy. Full article

(This article belongs to the Special Issue Highlights in Autophagy: From Basic Mechanisms to Human Disorder Treatments)

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18 pages, 4551 KiB

Open AccessArticle

High Dietary Phosphate Exacerbates and Acts Independently of Low Autophagy Activity in Pathological Cardiac Remodeling and Dysfunction

by Mingjun Shi, Sierra Shepard, Zhiyong Zhou, Jenny Maique, Olivia Seli, Orson W. Moe and Ming Chang Hu

Cells 2021, 10(4), 777; https://doi.org/10.3390/cells10040777 - 01 Apr 2021

Cited by 4 | Viewed by 2200

Abstract

High phosphate contributes to uremic cardiomyopathy. Abnormal autophagy is associated with the development and progression of heart disease. What is unknown is the effects of phosphate on autophagy and whether the ill effects of phosphate on cardiomyocytes are mediated by low autophagy. High [...] Read more.

High phosphate contributes to uremic cardiomyopathy. Abnormal autophagy is associated with the development and progression of heart disease. What is unknown is the effects of phosphate on autophagy and whether the ill effects of phosphate on cardiomyocytes are mediated by low autophagy. High (2.0% w/w)-phosphate diet reduced LC3 puncta in cardiomyocytes and ratio of LC3 II/I and increased p62 protein, indicating that autophagy activity was suppressed. Mice with cardiomyocyte-specific deletion of autophagy-related protein 5 (H-atg5^−/−) had reduced autophagy only in the heart, developed cardiac dysfunction with hypertrophy and fibrosis, and had a short lifespan. When H-atg5^−/− mice were fed a high-phosphate diet, they developed more apoptosis in cardiomyocytes, more severe cardiac remodeling, and shorter lifespan than normal phosphate-fed H-atg5^−/− mice, indicating that cardiac phosphotoxicity is imparted independently of atg5. In conclusion, although high phosphate suppresses autophagy, high phosphate and low autophagy independently trigger and additionally amplify cardiac remodeling and dysfunction. Full article

(This article belongs to the Special Issue Highlights in Autophagy: From Basic Mechanisms to Human Disorder Treatments)

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40 pages, 5419 KiB

Open AccessArticle

BAG3 Proteomic Signature under Proteostasis Stress

by Christof Hiebel, Elisabeth Stürner, Meike Hoffmeister, Georg Tascher, Mario Schwarz, Heike Nagel, Christian Behrends, Christian Münch and Christian Behl

Cells 2020, 9(11), 2416; https://doi.org/10.3390/cells9112416 - 04 Nov 2020

Cited by 13 | Viewed by 3990

Abstract

The multifunctional HSP70 co-chaperone BAG3 (BCL-2-associated athanogene 3) represents a key player in the quality control of the cellular proteostasis network. In response to stress, BAG3 specifically targets aggregation-prone proteins to the perinuclear aggresome and promotes their degradation via BAG3-mediated selective macroautophagy. [...] Read more.

The multifunctional HSP70 co-chaperone BAG3 (BCL-2-associated athanogene 3) represents a key player in the quality control of the cellular proteostasis network. In response to stress, BAG3 specifically targets aggregation-prone proteins to the perinuclear aggresome and promotes their degradation via BAG3-mediated selective macroautophagy. To adapt cellular homeostasis to stress, BAG3 modulates and functions in various cellular processes and signaling pathways. Noteworthy, dysfunction and deregulation of BAG3 and its pathway are pathophysiologically linked to myopathies, cancer, and neurodegenerative disorders. Here, we report a BAG3 proteomic signature under proteostasis stress. To elucidate the dynamic and multifunctional action of BAG3 in response to stress, we established BAG3 interactomes under basal and proteostasis stress conditions by employing affinity purification combined with quantitative mass spectrometry. In addition to the identification of novel potential BAG3 interactors, we defined proteins whose interaction with BAG3 was altered upon stress. By functional annotation and protein-protein interaction enrichment analysis of the identified potential BAG3 interactors, we confirmed the multifunctionality of BAG3 and highlighted its crucial role in diverse cellular signaling pathways and processes, ensuring cellular proteostasis and cell viability. These include protein folding and degradation, gene expression, cytoskeleton dynamics (including cell cycle and transport), as well as granulostasis, in particular. Full article

(This article belongs to the Special Issue Highlights in Autophagy: From Basic Mechanisms to Human Disorder Treatments)

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15 pages, 1518 KiB

Open AccessCommunication

In Vivo Remodeling of Altered Autophagy-Lysosomal Pathway by a Phosphopeptide in Lupus

by Fengjuan Wang, Inmaculada Tasset, Ana Maria Cuervo and Sylviane Muller

Cells 2020, 9(10), 2328; https://doi.org/10.3390/cells9102328 - 20 Oct 2020

Cited by 27 | Viewed by 4122

Abstract

The phosphopeptide P140/Lupuzor, which improves the course of lupus disease in mice and patients, targets chaperone-mediated autophagy (CMA), a selective form of autophagy that is abnormally upregulated in lupus-prone MRL/lpr mice. Administered intravenously to diseased mice, P140 reduces the expression level of two [...] Read more.

The phosphopeptide P140/Lupuzor, which improves the course of lupus disease in mice and patients, targets chaperone-mediated autophagy (CMA), a selective form of autophagy that is abnormally upregulated in lupus-prone MRL/lpr mice. Administered intravenously to diseased mice, P140 reduces the expression level of two major protein players of CMA, LAMP2A and HSPA8, and inhibits CMA in vitro in a cell line that stably expresses a CMA reporter. Here, we aimed to demonstrate that P140 also affects CMA in vivo and to unravel the precise cellular mechanism of how P140 interacts with the CMA process. MRL/lpr mice and CBA/J mice used as control received P140 or control peptides intravenously. Lysosome-enriched fractions of spleen or liver were prepared to examine lysosomal function. Highly purified lysosomes were further isolated and left to incubate with the CMA substrate to study at which cellular step P140 interacts with the CMA process. The data show that P140 effectively regulates CMA in vivo in MRL/lpr mice at the step of substrate lysosomal uptake and restores some alterations of defective lysosomes. For the first time, it is demonstrated that by occluding the intralysosome uptake of CMA substrates, a therapeutic molecule can attenuate excessive CMA activity in a pathological pro-inflammatory context and protect against hyperinflammation. This recovery effect of P140 on hyperactivated CMA is not only important for lupus therapy but potentially also for treating other (auto)inflammatory diseases, including neurologic and metabolic disorders, where CMA modulation would be highly beneficial. Full article

(This article belongs to the Special Issue Highlights in Autophagy: From Basic Mechanisms to Human Disorder Treatments)

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Review

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16 pages, 1061 KiB

Open AccessReview

Broad and Complex Roles of NBR1-Mediated Selective Autophagy in Plant Stress Responses

by Yan Zhang and Zhixiang Chen

Cells 2020, 9(12), 2562; https://doi.org/10.3390/cells9122562 - 30 Nov 2020

Cited by 24 | Viewed by 3971

Abstract

Selective autophagy is a highly regulated degradation pathway for the removal of specific damaged or unwanted cellular components and organelles such as protein aggregates. Cargo selectivity in selective autophagy relies on the action of cargo receptors and adaptors. In mammalian cells, two structurally [...] Read more.

Selective autophagy is a highly regulated degradation pathway for the removal of specific damaged or unwanted cellular components and organelles such as protein aggregates. Cargo selectivity in selective autophagy relies on the action of cargo receptors and adaptors. In mammalian cells, two structurally related proteins p62 and NBR1 act as cargo receptors for selective autophagy of ubiquitinated proteins including aggregation-prone proteins in aggrephagy. Plant NBR1 is the structural and functional homolog of mammalian p62 and NBR1. Since its first reports almost ten years ago, plant NBR1 has been well established to function as a cargo receptor for selective autophagy of stress-induced protein aggregates and play an important role in plant responses to a broad spectrum of stress conditions including heat, salt and drought. Over the past several years, important progress has been made in the discovery of specific cargo proteins of plant NBR1 and their roles in the regulation of plant heat stress memory, plant-viral interaction and special protein secretion. There is also new evidence for a possible role of NBR1 in stress-induced pexophagy, sulfur nutrient responses and abscisic acid signaling. In this review, we summarize these progresses and discuss the potential significance of NBR1-mediated selective autophagy in broad plant responses to both biotic and abiotic stresses. Full article

(This article belongs to the Special Issue Highlights in Autophagy: From Basic Mechanisms to Human Disorder Treatments)

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65 pages, 2267 KiB

Open AccessReview

Mitophagy in the Pathogenesis of Liver Diseases

by Po-Yuan Ke

Cells 2020, 9(4), 831; https://doi.org/10.3390/cells9040831 - 30 Mar 2020

Cited by 52 | Viewed by 9668

Abstract

Autophagy is a catabolic process involving vacuolar sequestration of intracellular components and their targeting to lysosomes for degradation, thus supporting nutrient recycling and energy regeneration. Accumulating evidence indicates that in addition to being a bulk, nonselective degradation mechanism, autophagy may selectively eliminate damaged [...] Read more.

Autophagy is a catabolic process involving vacuolar sequestration of intracellular components and their targeting to lysosomes for degradation, thus supporting nutrient recycling and energy regeneration. Accumulating evidence indicates that in addition to being a bulk, nonselective degradation mechanism, autophagy may selectively eliminate damaged mitochondria to promote mitochondrial turnover, a process termed “mitophagy”. Mitophagy sequesters dysfunctional mitochondria via ubiquitination and cargo receptor recognition and has emerged as an important event in the regulation of liver physiology. Recent studies have shown that mitophagy may participate in the pathogenesis of various liver diseases, such as liver injury, liver steatosis/fatty liver disease, hepatocellular carcinoma, viral hepatitis, and hepatic fibrosis. This review summarizes the current knowledge on the molecular regulations and functions of mitophagy in liver physiology and the roles of mitophagy in the development of liver-related diseases. Furthermore, the therapeutic implications of targeting hepatic mitophagy to design a new strategy to cure liver diseases are discussed. Full article

(This article belongs to the Special Issue Highlights in Autophagy: From Basic Mechanisms to Human Disorder Treatments)

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