Redundancy of human ATG4 protease isoforms in autophagy and LC3/GABARAP processing revealed in cells

Agrotis, Alexander; Pengo, Niccolò; Burden, Jemima J.; Ketteler, Robin

doi:10.1080/15548627.2019.1569925

Cited by 177 publications

(158 citation statements)

References 47 publications

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“…Previous researches suggested that the miR-376 mediated ATG4C silencing could suppress autophagy in breast cancer cells and hepatocarcinoma cells [31,32]. Recently, there was data implied that ATG4C had a limited role in autophagy [50]. In the current work, we observed that LC3-II expression was significantly reduced in the presence of BafA1 in sh-ATG4C cells, indicating impaired autophagic flux.…”

Section: Discussionsupporting

confidence: 44%

Knockdown ATG4C inhibits gliomas progression and promotes temozolomide chemosensitivity by suppressing autophagic flux

Wen

Zeng

Chen

et al. 2019

J Exp Clin Cancer Res

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Background: Gliomas are the most common primary tumors in central nervous system. Despite advances in diagnosis and therapy, the prognosis of glioma remains gloomy. Autophagy is a cellular catabolic process that degrades proteins and damaged organelles, which is implicated in tumorigenesis and tumor progression. Autophagy related 4C cysteine peptidase (ATG4C) is an autophagy regulator responsible for cleaving of pro-LC3 and delipidation of LC3 II. This study was designed to investigate the role of ATG4C in glioma progression and temozolomide (TMZ) chemosensitivity. Methods: The association between ATG4C mRNA expression and prognosis of gliomas patients was analyzed using the TCGA datasets. The role of ATG4C in proliferation, apoptosis, autophagy, and TMZ chemosensitivity were investigated by silencing ATG4C in vivo. Ectopic xenograft nude mice model was established to investigate the effects of ATG4C on glioma growth in vivo. Results: The median overall survival (OS) time of patients with higher ATG4C expression was significantly reduced (HR: 1.48, p = 9.91 × 10 − 7). ATG4C mRNA expression was evidently increased with the rising of glioma grade (p = 2.97 × 10 − 8). Knockdown ATG4C suppressed glioma cells proliferation by inducing cell cycle arrest at G1 phase. ATG4C depletion suppressed autophagy and triggered apoptosis through ROS accumulation. Depletion of ATG4C suppressed TMZ-activated autophagy and promoted sensitivity of glioma cells to TMZ. Additionally, ATG4C knockdown suppressed the growth of glioma remarkably in nude mice. Conclusion: ATG4C is a potential prognostic predictor for glioma patient. Targeting ATG4C may provide promising therapy strategies for gliomas treatment.

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Section: Discussionsupporting

confidence: 44%

Knockdown ATG4C inhibits gliomas progression and promotes temozolomide chemosensitivity by suppressing autophagic flux

Wen

Zeng

Chen

et al. 2019

J Exp Clin Cancer Res

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“…Beclin-1, a crucial regulator of autophagy, forms a complex with other autophagy proteins in order to mediate autophagosome assembly and to increase intracellular autophagic flux [ 33 , 34 ]. During autophagy, cytosolic microtubule-associated protein 1 light chain 3-I (LC3-I) is converted into microtubule-associated protein 1 light chain 3-II (LC3-II) and recruited to the autophagosomal membrane, with such conversion being an indicator of autophagosome formation [ 35 , 36 ]. In our study, the overexpression of MKP-5 rescued the PA-induced reduction in Beclin-1 observed at both 9 and 12 h post-treatment in Rin-m5f cells, whereas LC3-II levels were augmented only at 12 h post-PA treatment in Rin-MKP-5 relative to Rin-PC cells ( Figure 4 D).…”

Section: Resultsmentioning

confidence: 99%

MKP-5 Relieves Lipotoxicity-Induced Islet β-Cell Dysfunction and Apoptosis via Regulation of Autophagy

Zhao

et al. 2020

IJMS

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Mitogen-activated protein kinase phosphatase-5 (MKP-5) is a regulator of extracellular signaling that is known to regulate lipid metabolism. In this study, we found that obesity caused by a high-fat diet (HFD) decreased the expression of MKP-5 in the pancreas and primary islet cells derived from mice. Then, we further investigated the role of MKP-5 in the protection of islet cells from lipotoxicity by modulating MKP-5 expression. As a critical inducer of lipotoxicity, palmitic acid (PA) was used to treat islet β-cells. We found that MKP-5 overexpression restored PA-mediated autophagy inhibition in Rin-m5f cells and protected these cells from PA-induced apoptosis and dysfunction. Consistently, a lack of MKP-5 aggravated the adverse effects of lipotoxicity. Islet cells from HFD-fed mice were infected using recombinant adenovirus expressing MKP-5 (Ad-MKP-5), and we found that Ad-MKP-5 was able to alleviate HFD-induced apoptotic protein activation and relieve the HFD-mediated inhibition of functional proteins. Notably, HFD-mediated impairments in autophagic flux were restored by Ad-MKP-5 transduction. Furthermore, the autophagy inhibitor 3-methyladenine (3-MA) was used to treat Rin-m5f cells, confirming that the MKP-5 overexpression suppressed apoptosis, dysfunction, inflammatory response, and oxidative stress induced by PA via improving autophagic signaling. Lastly, employing c-Jun amino-terminal kinas (JNK), P38, or extracellular-regulated kinase (ERK) inhibitors, we established that the JNK and P38 MAPK pathways were involved in the MKP-5-mediated apoptosis, dysfunction, and autophagic inhibition observed in islet β cells in response to lipotoxicity.

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“…However, this model is complicated by the fact that ATG4B C74A very strongly binds to its substrates, acting as a sink that depletes LC3/GABARAPs from the cytoplasm. More recently, cell lines edited by clustered regularly interspaced palindromic repeats (CRISPR) technology, where one or a combination of all four mammalian ATG4 family members have been deleted, were reported [37,38]. In addition, a cell line with deletion of all major LC3/GABARAP proteins has been produced and studied with regards to their resistance to external stresses [44,45].…”

Section: Atg4b As Drug Targetmentioning

confidence: 99%

“…Here, we propose the autophagy-specific ATG4 proteases as a druggable class of enzymes that can overcome these limitations. The ATG4 proteases mediate processing of ubiquitin-like Atg8/LC3/GABARAP proteins involved in the formation and maturation of autophagosomes, the functional units of the autophagy pathway [37]. Here, we will perform a critical appraisal of ATG4B as drug target in cancers and discuss tools and reagents available for drug development.…”

Section: Introductionmentioning

confidence: 99%

On ATG4B as Drug Target for Treatment of Solid Tumours—The Knowns and the Unknowns

Agrotis

Ketteler

2019

Cells

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Autophagy is an evolutionary conserved stress survival pathway that has been shown to play an important role in the initiation, progression, and metastasis of multiple cancers; however, little progress has been made to date in translation of basic research to clinical application. This is partially due to an incomplete understanding of the role of autophagy in the different stages of cancer, and also to an incomplete assessment of potential drug targets in the autophagy pathway. While drug discovery efforts are on-going to target enzymes involved in the initiation phase of the autophagosome, e.g., unc51-like autophagy activating kinase (ULK)1/2, vacuolar protein sorting 34 (Vps34), and autophagy-related (ATG)7, we propose that the cysteine protease ATG4B is a bona fide drug target for the development of anti-cancer treatments. In this review, we highlight some of the recent advances in our understanding of the role of ATG4B in autophagy and its relevance to cancer, and perform a critical evaluation of ATG4B as a druggable cancer target.

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Redundancy of human ATG4 protease isoforms in autophagy and LC3/GABARAP processing revealed in cells

Cited by 177 publications

References 47 publications

Knockdown ATG4C inhibits gliomas progression and promotes temozolomide chemosensitivity by suppressing autophagic flux

Knockdown ATG4C inhibits gliomas progression and promotes temozolomide chemosensitivity by suppressing autophagic flux

MKP-5 Relieves Lipotoxicity-Induced Islet β-Cell Dysfunction and Apoptosis via Regulation of Autophagy

On ATG4B as Drug Target for Treatment of Solid Tumours—The Knowns and the Unknowns

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