scholarly journals Autophagy regulation by acetylation—implications for neurodegenerative diseases

2021 ◽  
Vol 53 (1) ◽  
pp. 30-41
Author(s):  
Sung Min Son ◽  
So Jung Park ◽  
Marian Fernandez-Estevez ◽  
David C. Rubinsztein
Keyword(s):  
Neurodegenerative Diseases ◽  
Posttranslational Modifications ◽  
Molecular Mechanisms ◽  
Membrane Vesicles ◽  
Cell Types ◽  
Double Membrane ◽  
Physiological Processes ◽  
Evolutionarily Conserved ◽  
Development And Aging ◽  
Catabolic Process

AbstractPosttranslational modifications of proteins, such as acetylation, are essential for the regulation of diverse physiological processes, including metabolism, development and aging. Autophagy is an evolutionarily conserved catabolic process that involves the highly regulated sequestration of intracytoplasmic contents in double-membrane vesicles called autophagosomes, which are subsequently degraded after fusing with lysosomes. The roles and mechanisms of acetylation in autophagy control have emerged only in the last few years. In this review, we describe key molecular mechanisms by which previously identified acetyltransferases and deacetylases regulate autophagy. We highlight how p300 acetyltransferase controls mTORC1 activity to regulate autophagy under starvation and refeeding conditions in many cell types. Finally, we discuss how altered acetylation may impact various neurodegenerative diseases in which many of the causative proteins are autophagy substrates. These studies highlight some of the complexities that may need to be considered by anyone aiming to perturb acetylation under these conditions.

scholarly journals Autophagy plays a double-edged sword role in liver diseases

2021 ◽  
Author(s):  
Jing-chao Zhou ◽  
Jing-lin Wang ◽  
Hao-zhen Ren ◽  
Xiao-lei Shi
Keyword(s):  
Liver Diseases ◽  
Alcoholic Hepatitis ◽  
Molecular Mechanisms ◽  
Membrane Vesicles ◽  
Building Blocks ◽  
Cell Types ◽  
Evolutionarily Conserved ◽  
Constitutive Process ◽  
New Strategies

Abstract As a highly evolutionarily conserved process, autophagy can be found in all types of eukaryotic cells. Such a constitutive process maintains cellular homeostasis in a wide variety of cell types through the encapsulation of damaged proteins or organelles into double-membrane vesicles. Autophagy not only simply eliminates materials but also serves as a dynamic recycling system that produces new building blocks and energy for cellular renovation and homeostasis. Previous studies have primarily recognized the role of autophagy in the degradation of dysfunctional proteins and unwanted organelles. However, there are findings of autophagy in physiological and pathological processes. In hepatocytes, autophagy is not only essential for homeostatic functions but also implicated in some diseases, such as viral hepatitis, alcoholic hepatitis, and hepatic failure. In the present review, we summarized the molecular mechanisms of autophagy and its role in several liver diseases and put forward several new strategies for the treatment of liver disease.

scholarly journals Biology, Pathophysiological Role, and Clinical Implications of Exosomes: A Critical Appraisal

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 99 ◽  
Author(s):  
Arif Jan ◽  
Safikur Rahman ◽  
Shahanavaj Khan ◽  
Sheikh Tasduq ◽  
Inho Choi
Keyword(s):  
Plasma Membranes ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Target Cells ◽  
Host Immune System ◽  
Messenger Rnas ◽  
Extracellular Milieu ◽  
Tumor Microenvironments ◽  
Physiological Processes ◽  
Antigen Presenting

Exosomes are membrane-enclosed entities of endocytic origin, which are generated during the fusion of multivesicular bodies (MVBs) and plasma membranes. Exosomes are released into the extracellular milieu or body fluids; this process was reported for mesenchymal, epithelial, endothelial, and different immune cells (B-cells and dendritic cells), and was reported to be correlated with normal physiological processes. The compositions and abundances of exosomes depend on their tissue origins and cell types. Exosomes range in size between 30 and 100 nm, and shuttle nucleic acids (DNA, messenger RNAs (mRNAs), microRNAs), proteins, and lipids between donor and target cells. Pathogenic microorganisms also secrete exosomes that modulate the host immune system and influence the fate of infections. Such immune-modulatory effect of exosomes can serve as a diagnostic biomarker of disease. On the other hand, the antigen-presenting and immune-stimulatory properties of exosomes enable them to trigger anti-tumor responses, and exosome release from cancerous cells suggests they contribute to the recruitment and reconstitution of components of tumor microenvironments. Furthermore, their modulation of physiological and pathological processes suggests they contribute to the developmental program, infections, and human diseases. Despite significant advances, our understanding of exosomes is far from complete, particularly regarding our understanding of the molecular mechanisms that subserve exosome formation, cargo packaging, and exosome release in different cellular backgrounds. The present study presents diverse biological aspects of exosomes, and highlights their diagnostic and therapeutic potentials.

scholarly journals Autophagy in Skin Diseases

Dermatology ◽  
2019 ◽  
Vol 235 (5) ◽  
pp. 380-389 ◽  
Author(s):  
Yeye Guo ◽  
Xu Zhang ◽  
Tianhao Wu ◽  
Xing Hu ◽  
Juan Su ◽  
...  
Keyword(s):  
Skin Diseases ◽  
Membrane Vesicles ◽  
Cellular Homeostasis ◽  
Double Membrane ◽  
Adaptive Process ◽  
Evolutionarily Conserved

Autophagy, or self-eating, is an evolutionarily conserved process in which cytosol and organelles are sequestered within double-membrane vesicles that deliver the contents to the lysosome/vacuole for the degradation and recycling of cytoplasmic components in eukaryotes. It is well recognized that autophagy plays an important role in maintaining cellular homeostasis under physiological and pathophysiological con­ditions and the upregulation of autophagy may serve as an adaptive process to provide nutrients and energy when under stresses. Recently, studies have illustrated that autophagy is intricately related to skin diseases. This review provides a brief synopsis of the process of autophagy and aims to elucidate the roles of autophagy in different skin diseases and to highlight the need for increased research in the field.

scholarly journals The Interplay of Reovirus with Autophagy

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Hung-Chuan Chiu ◽  
Sarah Richart ◽  
Fong-Yuan Lin ◽  
Wei-Li Hsu ◽  
Hung-Jen Liu
Keyword(s):  
Infectious Diseases ◽  
Membrane Vesicles ◽  
Protein Aggregates ◽  
Degradation Pathway ◽  
Cytoplasmic Protein ◽  
Cellular Homeostasis ◽  
Double Membrane ◽  
Protein Substrates ◽  
Reovirus Infection ◽  
Physiological Processes

Autophagy participates in multiple fundamental physiological processes, including survival, differentiation, development, and cellular homeostasis. It eliminates cytoplasmic protein aggregates and damaged organelles by triggering a series of events: sequestering the protein substrates into double-membrane vesicles, fusing the vesicles with lysosomes, and then degrading the autophagic contents. This degradation pathway is also involved in various disorders, for instance, cancers and infectious diseases. This paper provides an overview of modulation of autophagy in the course of reovirus infection and also the interplay of autophagy and reovirus.

scholarly journals Protein Posttranslational Modifications: Roles in Aging and Age-Related Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-19 ◽  
Author(s):  
Ana L. Santos ◽  
Ariel B. Lindner
Keyword(s):  
Posttranslational Modifications ◽  
Molecular Mechanisms ◽  
Molecular Processes ◽  
Progressive Decline ◽  
Age Related ◽  
Evolutionarily Conserved ◽  
Protein Posttranslational Modifications ◽  
Aging Models ◽  
The Relationship

Aging is characterized by the progressive decline of biochemical and physiological function in an individual. Consequently, aging is a major risk factor for diseases like cancer, obesity, and type 2 diabetes. The cellular and molecular mechanisms of aging are not well understood, nor is the relationship between aging and the onset of diseases. One of the hallmarks of aging is a decrease in cellular proteome homeostasis, allowing abnormal proteins to accumulate. This phenomenon is observed in both eukaryotes and prokaryotes, suggesting that the underlying molecular processes are evolutionarily conserved. Similar protein aggregation occurs in the pathogenesis of diseases like Alzheimer’s and Parkinson’s. Further, protein posttranslational modifications (PTMs), either spontaneous or physiological/pathological, are emerging as important markers of aging and aging-related diseases, though clear causality has not yet been firmly established. This review presents an overview of the interplay of PTMs in aging-associated molecular processes in eukaryotic aging models. Understanding PTM roles in aging could facilitate targeted therapies or interventions for age-related diseases. In addition, the study of PTMs in prokaryotes is highlighted, revealing the potential of simple prokaryotic models to uncover complex aging-associated molecular processes in the emerging field of microbiogerontology.

Omegasomes: PI3P platforms that manufacture autophagosomes

2013 ◽  
Vol 55 ◽  
pp. 17-27 ◽  
Author(s):  
Rebecca Roberts ◽  
Nicholas T. Ktistakis
Keyword(s):  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Membrane Vesicles ◽  
Double Membrane ◽  
Survival Pathway ◽  
Membrane Compartments ◽  
Specific Control ◽  
Phosphatidylinositol 3

Autophagy is a conserved survival pathway, which cells and tissues will activate during times of stress. It is characterized by the formation of double-membrane vesicles called autophagosomes inside the cytoplasm. The molecular mechanisms and the signalling components involved require specific control to ensure correct activation. The present chapter describes the formation of autophagosomes from within omegasomes, newly identified membrane compartments enriched in PI3P (phosphatidylinositol 3-phosphate) that serve as platforms for the formation of at least some autophagosomes. We discuss the signalling events required to nucleate the formation of omegasomes as well as the protein complexes involved.

scholarly journals Pex3 confines pexophagy receptor activity of Atg36 to peroxisomes by regulating Hrr25-mediated phosphorylation and proteasomal degradation

2020 ◽  
Vol 295 (48) ◽  
pp. 16292-16298
Author(s):  
Sota Meguro ◽  
Xizhen Zhuang ◽  
Hiromi Kirisako ◽  
Hitoshi Nakatogawa
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Recombinant Proteins ◽  
Posttranslational Modifications ◽  
Membrane Vesicles ◽  
Proteasomal Degradation ◽  
Regulatory Mechanisms ◽  
Autophagosome Formation ◽  
Peroxisomal Membrane ◽  
Double Membrane ◽  
Selective Autophagy

In macroautophagy (hereafter autophagy), cytoplasmic molecules and organelles are randomly or selectively sequestered within double-membrane vesicles called autophagosomes and delivered to lysosomes or vacuoles for degradation. In selective autophagy, the specificity of degradation targets is determined by autophagy receptors. In the budding yeast Saccharomyces cerevisiae, autophagy receptors interact with specific targets and Atg11, resulting in the recruitment of a protein complex that initiates autophagosome formation. Previous studies have revealed that autophagy receptors are regulated by posttranslational modifications. In selective autophagy of peroxisomes (pexophagy), the receptor Atg36 localizes to peroxisomes by binding to the peroxisomal membrane protein Pex3. We previously reported that Atg36 is phosphorylated by Hrr25 (casein kinase 1δ), increasing the Atg36–Atg11 interaction and thereby stimulating pexophagy initiation. However, the regulatory mechanisms underlying Atg36 phosphorylation are unknown. Here, we show that Atg36 phosphorylation is abolished in cells lacking Pex3 or expressing a Pex3 mutant defective in the interaction with Atg36, suggesting that the interaction with Pex3 is essential for the Hrr25-mediated phosphorylation of Atg36. Using recombinant proteins, we further demonstrated that Pex3 directly promotes Atg36 phosphorylation by Hrr25. A co-immunoprecipitation analysis revealed that the interaction of Atg36 with Hrr25 depends on Pex3. These results suggest that Pex3 increases the Atg36–Hrr25 interaction and thereby stimulates Atg36 phosphorylation on the peroxisomal membrane. In addition, we found that Pex3 binding protects Atg36 from proteasomal degradation. Thus, Pex3 confines Atg36 activity to the peroxisome by enhancing its phosphorylation and stability on this organelle.

scholarly journals Mitochondria and Mitochondrial DNA: Key Elements in the Pathogenesis and Exacerbation of the Inflammatory State Caused by COVID-19

Medicina ◽  
2021 ◽  
Vol 57 (9) ◽  
pp. 928
Author(s):  
José J. Valdés-Aguayo ◽  
Idalia Garza-Veloz ◽  
José I. Badillo-Almaráz ◽  
Sofia Bernal-Silva ◽  
Maria C. Martínez-Vázquez ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Viral Genome ◽  
Molecular Mechanisms ◽  
Membrane Vesicles ◽  
Defense System ◽  
Mt Dna ◽  
Double Membrane ◽  
Cell Defense ◽  
Inflammatory State ◽  
Potential Area

Background and Objectives. The importance of mitochondria in inflammatory pathologies, besides providing energy, is associated with the release of mitochondrial damage products, such as mitochondrial DNA (mt-DNA), which may perpetuate inflammation. In this review, we aimed to show the importance of mitochondria, as organelles that produce energy and intervene in multiple pathologies, focusing mainly in COVID-19 and using multiple molecular mechanisms that allow for the replication and maintenance of the viral genome, leading to the exacerbation and spread of the inflammatory response. The evidence suggests that mitochondria are implicated in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which forms double-membrane vesicles and evades detection by the cell defense system. These mitochondrion-hijacking vesicles damage the integrity of the mitochondrion’s membrane, releasing mt-DNA into circulation and triggering the activation of innate immunity, which may contribute to an exacerbation of the pro-inflammatory state. Conclusions. While mitochondrial dysfunction in COVID-19 continues to be studied, the use of mt-DNA as an indicator of prognosis and severity is a potential area yet to be explored.

Microtubule-modulating agents in the fight against neurodegeneration: Will it ever work?

2021 ◽  
Vol 19 ◽  
Author(s):  
Ahmed Soliman ◽  
Lidia Bakota ◽  
Roland Brandt
Keyword(s):  
Neurodegenerative Diseases ◽  
Posttranslational Modifications ◽  
Drug Target ◽  
Neuronal Cell ◽  
Cell Types ◽  
Transport Processes ◽  
Microtubule Stability ◽  
Age Related ◽  
Neuroprotective Strategy ◽  
Structural Determinant

: The microtubule skeleton plays an essential role in nerve cells as the most important structural determinant of morphology and as a highway for axonal transport processes. Many neurodegenerative diseases are characterized by changes in the structure and organization of microtubules and microtubule-regulating proteins such as the microtubule-associated protein tau, which exhibits characteristic changes in a whole class of diseases collectively referred to as tauopathies. Changes in the dynamics of microtubules appear to occur early under neurodegenerative conditions and are also likely to contribute to age-related dysfunction of neurons. Thus, modulating microtubule dynamics and correcting impaired microtubule stability can be a useful neuroprotective strategy to counteract disruption of the microtubule system in disease and aging. In this article, we review current microtubule-directed approaches for the treatment of neurodegenerative diseases with microtubules as drug target, tau as drug target, and posttranslational modifications as potential modifiers of the microtubule system. We discuss limitations of the approaches that can be traced back to the rather unspecific mechanism of action, which causes undesirable side effects on non-neuronal cell types or which are due to the disruption of non-microtubule-related interactions. We also develop some thoughts on how the specificity of the approaches can be improved and what further targets could be used for modulating substances.

scholarly journals Molecular Background of Leak K+ Currents: Two-Pore Domain Potassium Channels

2010 ◽  
Vol 90 (2) ◽  
pp. 559-605 ◽  
Author(s):  
Péter Enyedi ◽  
Gábor Czirják
Keyword(s):  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Detailed Examination ◽  
Resting Membrane Potential ◽  
Membrane Stretch ◽  
Physiological Processes ◽  
Pore Domain ◽  
K Currents

Two-pore domain K+ (K2P) channels give rise to leak (also called background) K+ currents. The well-known role of background K+ currents is to stabilize the negative resting membrane potential and counterbalance depolarization. However, it has become apparent in the past decade (during the detailed examination of the cloned and corresponding native K2P channel types) that this primary hyperpolarizing action is not performed passively. The K2P channels are regulated by a wide variety of voltage-independent factors. Basic physicochemical parameters (e.g., pH, temperature, membrane stretch) and also several intracellular signaling pathways substantially and specifically modulate the different members of the six K2P channel subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). The deep implication in diverse physiological processes, the circumscribed expression pattern of the different channels, and the interesting pharmacological profile brought the K2P channel family into the spotlight. In this review, we focus on the physiological roles of K2P channels in the most extensively investigated cell types, with special emphasis on the molecular mechanisms of channel regulation.

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