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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 15 May 2024 | Viewed by 12288

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Special Issue Editor

Prof. Dr. Maria Ines Vaccaro

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Guest Editor

National Council for Scientific and Technical Research, Center for Medical Education and Clinical Research University Institute, University of Buenos Aires, Buenos Aires C1180, Argentina
Interests: autophagy; selective autophagy; secretory autophagy; physiology; pathophysiology; pancreatic diseases

Special Issue Information

Dear Colleagues,

Autophagy is a cellular catabolic process that sequesters and delivers cytoplasmic components to the lysosome for degradation. By recycling cytoplasmic constituents, autophagy controls cellular bioenergetics and tissue remodeling. In addition, autophagy allows the selective elimination of misfolded proteins, protein aggregates, damaged organelles, intracellular pathogens, and lipid droplets. This pathway is called selective autophagy and has relevance in the cell response to disease. Independently of the lysosomal degradation, the autophagic machinery can be involved in other processes, such as the unconventional secretion including extracellular vesicles, the mechanism related to vesicle trafficking such as phagocytosis, and the regulation of inflammatory signaling such as the formation and clearance of inflammasome. Although a core group of evolutionarily conserved AuTophaGy-related proteins is involved in autophagosome biogenesis, an increasing number of new autophagy-related proteins are being characterized in certain physiological and pathological situations or in specific selective or secretory autophagic processes. Furthermore, posttranscriptional as well as post translational modification of ATG molecules are emerging regulatory mechanisms in physiological and pathological roles od autophagy.

In this Special Issue of IJMS, the focus will be on molecular research in autophagy. Suitable topics include, but are not limited to molecular processes involved in the multiple roles of autophagy in physiological and pathological situations. Furthermore, the clinical and pharmacological applications of the research in molecular pathways related to autophagy are welcome for this Special Issue of IJMS.

Prof. Dr. Maria Ines Vaccaro
Guest Editor

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Keywords

ATG molecules
transcriptional and post translational modification
selective pathways
secretory pathways
complexes diseases
degenerative processes
inflammatory diseases
tumorigenesis
metabolism
proteostasis

Published Papers (7 papers)

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Research

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22 pages, 44705 KiB

Open AccessArticle

Missing WD40 Repeats in ATG16L1 Delays Canonical Autophagy and Inhibits Noncanonical Autophagy

by Jiuge Tang, Dongmei Fang, Jialing Zhong and Min Li

Int. J. Mol. Sci. 2024, 25(8), 4493; https://doi.org/10.3390/ijms25084493 - 19 Apr 2024

Viewed by 324

Abstract

Canonical autophagy is an evolutionarily conserved process that forms double-membrane structures and mediates the degradation of long-lived proteins (LLPs). Noncanonical autophagy (NCA) is an important alternative pathway involving the formation of microtubule-associated protein 1 light chain 3 (LC3)-positive structures that are independent of partial core autophagy proteins. NCA has been defined by the conjugation of ATG8s to single membranes (CASM). During canonical autophagy and NCA/CASM, LC3 undergoes a lipidation modification, and ATG16L1 is a crucial protein in this process. Previous studies have reported that the WDR domain of ATG16L1 is not necessary for canonical autophagy. However, our study found that WDR domain deficiency significantly impaired LLP degradation in basal conditions and slowed down LC3-II accumulation in canonical autophagy. We further demonstrated that the observed effect was due to a reduced interaction between ATG16L1 and FIP200/WIPI2, without affecting lysosome function or fusion. Furthermore, we also found that the WDR domain of ATG16L1 is crucial for chemical-induced NCA/CASM. The results showed that removing the WDR domain or introducing the K490A mutation in ATG16L1 significantly inhibited the NCA/CASM, which interrupted the V-ATPase-ATG16L1 axis. In conclusion, this study highlights the significance of the WDR domain of ATG16L1 for both canonical autophagy and NCA functions, improving our understanding of its role in autophagy. Full article

(This article belongs to the Special Issue Molecular Research on Autophagy)

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15 pages, 6854 KiB

Open AccessArticle

Investigating the Association between the Autophagy Markers LC3B, SQSTM1/p62, and DRAM and Autophagy-Related Genes in Glioma

by Farheen Danish, Muhammad Asif Qureshi, Talat Mirza, Wajiha Amin, Sufiyan Sufiyan, Sana Naeem, Fatima Arshad and Nouman Mughal

Int. J. Mol. Sci. 2024, 25(1), 572; https://doi.org/10.3390/ijms25010572 - 01 Jan 2024

Viewed by 1026

Abstract

High-grade gliomas are extremely fatal tumors, marked by severe hypoxia and therapeutic resistance. Autophagy is a cellular degradative process that can be activated by hypoxia, ultimately resulting in tumor advancement and chemo-resistance. Our study aimed to examine the link between autophagy markers’ expression in low-grade gliomas (LGGs) and high-grade gliomas (HGGs). In 39 glioma cases, we assessed the protein expression of autophagy markers LC3B, SQSTM1/p62, and DRAM by immunohistochemistry (IHC) and the mRNA expression of the autophagy genes PTEN, PI3K, AKT, mTOR, ULK1, ULK2, UVRAG, Beclin 1, and VPS34 using RT-qPCR. LC3B, SQSTM1/p62, and DRAM expression were positive in 64.1%, 51.3%, and 28.2% of glioma cases, respectively. The expression of LC3B and SQSTM1/p62 was notably higher in HGGs compared to LGGs. VPS34 exhibited a significant differential expression, displaying increased fold change in HGGs compared to LGGs. Additionally, it exhibited robust positive associations with Beclin1 (rs = 0.768), UVRAG (rs = 0.802), and ULK2 (rs = 0.786) in HGGs. This underscores a potential association between autophagy and the progression of gliomas. We provide preliminary data for the functional analysis of autophagy using a cell culture model and to identify potential targets for therapeutic interventions. Full article

(This article belongs to the Special Issue Molecular Research on Autophagy)

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18 pages, 3726 KiB

Open AccessArticle

MAGED2 Depletion Promotes Stress-Induced Autophagy by Impairing the cAMP/PKA Pathway

by Sadiq Nasrah, Aline Radi, Johanna K. Daberkow, Helmut Hummler, Stefanie Weber, Elie Seaayfan and Martin Kömhoff

Int. J. Mol. Sci. 2023, 24(17), 13433; https://doi.org/10.3390/ijms241713433 - 30 Aug 2023

Cited by 1 | Viewed by 2864

Abstract

Melanoma-associated antigen D2 (MAGED2) plays an essential role in activating the cAMP/PKA pathway under hypoxic conditions, which is crucial for stimulating renal salt reabsorption and thus explaining the transient variant of Bartter’s syndrome. The cAMP/PKA pathway is also known to regulate autophagy, a lysosomal degradation process induced by cellular stress. Previous studies showed that two members of the melanoma-associated antigens MAGE-family inhibit autophagy. To explore the potential role of MAGED2 in stress-induced autophagy, specific MAGED2-siRNA were used in HEK293 cells under physical hypoxia and oxidative stress (cobalt chloride, hypoxia mimetic). Depletion of MAGED2 resulted in reduced p62 levels and upregulation of both the autophagy-related genes (ATG5 and ATG12) as well as the autophagosome marker LC3II compared to control siRNA. The increase in the autophagy markers in MAGED2-depleted cells was further confirmed by leupeptin-based assay which concurred with the highest LC3II accumulation. Likewise, under hypoxia, immunofluorescence in HEK293, HeLa and U2OS cell lines demonstrated a pronounced accumulation of LC3B puncta upon MAGED2 depletion. Moreover, LC3B puncta were absent in human fetal control kidneys but markedly expressed in a fetal kidney from a MAGED2-deficient subject. Induction of autophagy with both physical hypoxia and oxidative stress suggests a potentially general role of MAGED2 under stress conditions. Various other cellular stressors (brefeldin A, tunicamycin, 2-deoxy-D-glucose, and camptothecin) were analyzed, which all induced autophagy in the absence of MAGED2. Forskolin (FSK) inhibited, whereas GNAS Knockdown induced autophagy under hypoxia. In contrast to other MAGE proteins, MAGED2 has an inhibitory role on autophagy only under stress conditions. Hence, a prominent role of MAGED2 in the regulation of autophagy under stress conditions is evident, which may also contribute to impaired fetal renal salt reabsorption by promoting autophagy of salt-transporters in patients with MAGED2 mutation. Full article

(This article belongs to the Special Issue Molecular Research on Autophagy)

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22 pages, 5096 KiB

Open AccessArticle

Ubiquitination Is a Novel Post-Translational Modification of VMP1 in Autophagy of Human Tumor Cells

by Felipe J. Renna, Juliana H. Enriqué Steinberg, Claudio D. Gonzalez, Maria Manifava, Mariana S. Tadic, Tamara Orquera, Carolina V. Vecino, Alejandro Ropolo, Daniele Guardavaccaro, Mario Rossi, Nicholas T. Ktistakis and Maria I. Vaccaro

Int. J. Mol. Sci. 2023, 24(16), 12981; https://doi.org/10.3390/ijms241612981 - 19 Aug 2023

Cited by 1 | Viewed by 1622

Abstract

Autophagy is a tightly regulated catabolic process involved in the degradation and recycling of proteins and organelles. Ubiquitination plays an important role in the regulation of autophagy. Vacuole Membrane Protein 1 (VMP1) is an essential autophagy protein. The expression of VMP1 in pancreatic cancer stem cells carrying the activated Kirsten rat sarcoma viral oncogene homolog (KRAS) triggers autophagy and enables therapy resistance. Using biochemical and cellular approaches, we identified ubiquitination as a post-translational modification of VMP1 from the initial steps in autophagosome biogenesis. VMP1 remains ubiquitinated as part of the autophagosome membrane throughout autophagic flux until autolysosome formation. However, VMP1 is not degraded by autophagy, nor by the ubiquitin–proteasomal system. Mass spectrometry and immunoprecipitation showed that the cell division cycle protein cdt2 (Cdt2), the substrate recognition subunit of the E3 ligase complex associated with cancer, cullin–RING ubiquitin ligase complex 4 (CRL4), is a novel interactor of VMP1 and is involved in VMP1 ubiquitination. VMP1 ubiquitination decreases under the CRL inhibitor MLN4924 and increases with Cdt2 overexpression. Moreover, VMP1 recruitment and autophagosome formation is significantly affected by CRL inhibition. Our results indicate that ubiquitination is a novel post-translational modification of VMP1 during autophagy in human tumor cells. VMP1 ubiquitination may be of clinical relevance in tumor-cell-therapy resistance. Full article

(This article belongs to the Special Issue Molecular Research on Autophagy)

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18 pages, 3328 KiB

Open AccessArticle

Intervention of Dietary Protein Levels on Muscle Quality, Antioxidation, and Autophagy in the Muscles of Triploid Crucian Carp (Carassius carassius Triploid)

by Zhimin He, Yuyang Cai, Yang Xiao, Shenping Cao, Gaode Zhong, Xinting Li, Yanfang Li, Junhan Luo, Jianzhou Tang, Fufa Qu, Zhen Liu and Suchun Liu

Int. J. Mol. Sci. 2023, 24(15), 12043; https://doi.org/10.3390/ijms241512043 - 27 Jul 2023

Cited by 1 | Viewed by 869

Abstract

The aim of this study is to investigate the effect of dietary protein levels on flesh quality, oxidative stress, and autophagy status in the muscles of triploid crucian carp (Carassius carassius triploid), and the related molecular mechanisms. Six experimental diets with different protein levels (26%, 29%, 32%, 35%, 38%, 41%) were formulated. A total of 540 fish with an initial weight of 11.79 ± 0.09 g were randomly assigned to 18 cages and six treatments with three replicates of 30 fish each for 8 weeks feeding. It could be found that the whole-body ash content significantly increased in high protein level groups (p < 0.05). The 29% dietary protein level group exhibited the highest muscle moisture, although there was an inconspicuous decrease in the chewiness of the muscles when compared with the other groups. The dietary protein level influenced the content of free amino acids and nucleotides, especially the content of flavor amino acids, which exhibited an increasing tendency along with the increasing protein level, such as alanine and glutamic acid, while the flavor nucleotides showed different fluctuation trends. Moreover, the genes related to muscle development were shown to be influenced by the dietary protein level, especially the expression of MRF4, which was up-regulated with the increasing dietary protein levels. The 29% dietary protein level promoted the majority of analyzed muscle genes expression to the highest level when compared to other dietary levels, except the Myostain, whose expression reached its highest at 38% dietary protein levels. Furthermore, the effect of dietary protein levels on antioxidant signaling pathway genes were also examined. High protein levels would boost the expression of GSTα; GPX1 and GPX4α mRNA expression showed the highest level at the 32% dietary protein group. The increasing dietary protein level decreased both mRNA and protein expressions of Nrf2 by up-regulating Keap1. Autophagy-related gene expression levels reached the peak at 32% dietary protein level, as evidenced by a similar change in protein expression of FoxO1. In summary, muscle nutritional composition, antioxidative pathways, and autophagy levels were affected by the dietary protein levels. A total of 29–32% dietary protein level would be the appropriate level range to improve muscle quality and promote the antioxidant and autophagy capacity of triploid crucian carp muscles. Full article

(This article belongs to the Special Issue Molecular Research on Autophagy)

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Review

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19 pages, 934 KiB

Open AccessReview

Autophagy Regulators in Cancer

by Juan Zhang, Qian Xiang, Man Wu, Yuan-Zhi Lao, Yan-Fang Xian, Hong-Xi Xu and Zhi-Xiu Lin

Int. J. Mol. Sci. 2023, 24(13), 10944; https://doi.org/10.3390/ijms241310944 - 30 Jun 2023

Cited by 2 | Viewed by 1851

Abstract

Autophagy plays a complex impact role in tumor initiation and development. It serves as a double-edged sword by supporting cell survival in certain situations while also triggering autophagic cell death in specific cellular contexts. Understanding the intricate functions and mechanisms of autophagy in tumors is crucial for guiding clinical approaches to cancer treatment. Recent studies highlight its significance in various aspects of cancer biology. Autophagy enables cancer cells to adapt to and survive unfavorable conditions by recycling cellular components. However, excessive or prolonged autophagy can lead to the self-destruction of cancer cells via a process known as autophagic cell death. Unraveling the molecular mechanisms underlying autophagy regulation in cancer is crucial for the development of targeted therapeutic interventions. In this review, we seek to present a comprehensive summary of current knowledge regarding autophagy, its impact on cancer cell survival and death, and the molecular mechanisms involved in the modulation of autophagy for cancer therapy. Full article

(This article belongs to the Special Issue Molecular Research on Autophagy)

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17 pages, 1589 KiB

Open AccessReview

Autophagy in Inflammatory Response against SARS-CoV-2

by Roxana Resnik, Fabiana Lopez Mingorance, Francisco Rivera, Florencia Mitchell, Claudio D. Gonzalez and Maria I. Vaccaro

Int. J. Mol. Sci. 2023, 24(5), 4928; https://doi.org/10.3390/ijms24054928 - 03 Mar 2023

Cited by 5 | Viewed by 2361

Abstract

The coronavirus disease pandemic, which profoundly reshaped the world in 2019 (COVID-19), and is currently ongoing, has affected over 200 countries, caused over 500 million cumulative cases, and claimed the lives of over 6.4 million people worldwide as of August 2022. The causative agent is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Depicting this virus’ life cycle and pathogenic mechanisms, as well as the cellular host factors and pathways involved during infection, has great relevance for the development of therapeutic strategies. Autophagy is a catabolic process that sequesters damaged cell organelles, proteins, and external invading microbes, and delivers them to the lysosomes for degradation. Autophagy would be involved in the entry, endo, and release, as well as the transcription and translation, of the viral particles in the host cell. Secretory autophagy would also be involved in developing the thrombotic immune-inflammatory syndrome seen in a significant number of COVID-19 patients that can lead to severe illness and even death. This review aims to review the main aspects that characterize the complex and not yet fully elucidated relationship between SARS-CoV-2 infection and autophagy. It briefly describes the key concepts regarding autophagy and mentions its pro- and antiviral roles, while also noting the reciprocal effect of viral infection in autophagic pathways and their clinical aspects. Full article

(This article belongs to the Special Issue Molecular Research on Autophagy)

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