Insights on autophagosome–lysosome tethering from structural and biochemical characterization of human autophagy factor EPG5

Nam, Sung Eun; Cheung, Yiu Wing Sunny; Nguyen, Thanh Ngoc; Gong, Michael C.; Chan, Sherilynn F.; Lazarou, Michael; Yip, Calvin K.

doi:10.1038/s42003-021-01830-x

Cited by 13 publications

(14 citation statements)

References 75 publications

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“…This mutation causes an amino acid substitution (p.Gln336Arg) which is thought to cause alternative splicing, maintaining a normally spliced product in 25% of the transcribed RNA, leading to a full length EPG5 protein, while 75% of the mRNA undergoes nonsense mediated decay due to aberrant spliced isoforms ( Byrne et al, 2016b ; Kane et al, 2016 ). Furthermore, it has been shown that this substitution maintains the overall structure, thermal stability and binding capacities of the proteins to GABARAP-y ( Nam et al, 2021 ). The remaining functioning isoform may explain the previously reported milder phenotype with prolonged survival ( Byrne et al, 2016a ; Vojcek et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Vici syndrome in Israel: Clinical and molecular insights

Chorin

Hirsch²,

Rock³

et al. 2022

Front. Genet.

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Introduction: Vici Syndrome is a rare, severe, neurodevelopmental/neurodegenerative disorder with multi-systemic manifestations presenting in infancy. It is mainly characterized by global developmental delay, seizures, agenesis of the corpus callosum, hair and skin hypopigmentation, bilateral cataract, and varying degrees of immunodeficiency, among other features. Vici Syndrome is caused by biallelic pathogenic variants in EPG5, resulting in impaired autophagy. Thus far, the condition has been reported in less than a hundred individuals.Objective and Methods: We aimed to characterize the clinical and molecular findings in individuals harboring biallelic EPG5 variants, recruited from four medical centers in Israel. Furthermore, we aimed to utilize a machine learning-based tool to assess facial features of Vici syndrome.Results: Eleven cases of Vici Syndrome from five unrelated families, one of which was diagnosed prenatally with subsequent termination of pregnancy, were recruited. A total of five disease causing variants were detected in EPG5: two novel: c.2554-5A>G and c.1461delC; and 3 previously reported: c.3447G>A, c.5993C>G, and c.1007A>G, the latter previously identified in several patients of Ashkenazi-Jewish (AJ) descent. Amongst 140,491 individuals screened by the Dor Yeshorim Program, we show that the c.1007A>G variant has an overall carrier frequency of 0.45% (1 in 224) among AJ individuals. Finally, based on two-dimensional facial photographs of individuals with Vici syndrome (n = 19), a composite facial mask was created using the DeepGestalt algorithm, illustrating facial features typical of this disorder.Conclusion: We report on ten children and one fetus from five unrelated families, affected with Vici syndrome, and describe prenatal and postnatal characteristics. Our findings contribute to the current knowledge regarding the molecular basis and phenotypic features of this rare syndrome. Additionally, the deep learning-based facial gestalt adds to the clinician’s diagnostic toolbox and may aid in facilitating identification of affected individuals.

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Section: Discussionmentioning

confidence: 99%

Vici syndrome in Israel: Clinical and molecular insights

Chorin

Hirsch²,

Rock³

et al. 2022

Front. Genet.

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“…It is noteworthy that tethering factors such as the EPG5 and HOPS complex also play critical effects in regulating the autophagosome-lysosome fusion. 103,110 Current studies on incomplete autophagy are generally focused on a few proteins such as STX17, SNAP29, and VAMP8, but the role of tethering factors was not investigated in the process of incomplete autophagy (Table 1). Therefore, analysing the distinctive roles of tethering factors in the process of incomplete autophagy needs to be paid attention in future research.…”

Section: Inhibiting Gtpases and Snaresmentioning

confidence: 99%

Incomplete autophagy: Trouble is a friend

Zhang

Cao

Qiu

et al. 2022

Medicinal Research Reviews

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Incomplete autophagy is an impaired self‐eating process of intracellular macromolecules and organelles in which accumulated autophagosomes do not fuse with lysosomes for degradation, resulting in the blockage of autophagic flux. In this review, we summarized the literature over the past decade describing incomplete autophagy, and found that different from the double‐edged sword effect of general autophagy on promoting cell survival or death, incomplete autophagy plays a crucial role in disrupting cellular homeostasis, and promotes only cell death. What matters is that incomplete autophagy is closely relevant to the pathogenesis and progression of various human diseases, which, meanwhile, intimately linking to the pharmacologic and toxicologic effects of several compounds. Here, we comprehensively reviewed the latest progress of incomplete autophagy on molecular mechanisms and signaling pathways. Moreover, implications of incomplete autophagy for pharmacotherapy are also discussed, which has great relevance for our understanding of the distinctive role of incomplete autophagy in cellular physiology and disease. Consequently, targeting incomplete autophagy may contribute to the development of novel generation therapeutic agents for diverse human diseases.

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“…EPG5, a less noted protein, was first identified as an autophagy-related gene during clinical genetic analysis, which reported that EPG5 mutation causes a multisystem disorder termed Vici syndrome, characterized by abnormalities in the brain, immune system, and reduced melanin production. Subsequent studies showed that EPG5 acts as a tethering factor being recruited to the lysosomes/late endosomes by Rab-GTPase, which promotes membrane fusion by stabilizing the trans-SNARE complex [ 90 ].…”

Section: Secretory Autophagy and Exosome Biogenesis In Melanoma: Two Sides Of The Same Coin?mentioning

confidence: 99%

Secretory Autophagy Forges a Therapy Resistant Microenvironment in Melanoma

Bustos

Santos

Chammas

et al. 2022

Cancers

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Melanoma is the most aggressive skin cancer characterized by high mutational burden and large heterogeneity. Cancer cells are surrounded by a complex environment, critical to tumor establishment and progression. Thus, tumor-associated stromal components can sustain tumor demands or impair cancer cell progression. One way to manage such processes is through the regulation of autophagy, both in stromal and tumor cells. Autophagy is a catabolic mechanism that provides nutrients and energy, and it eliminates damaged organelles by degradation and recycling of cellular elements. Besides this primary function, autophagy plays multiple roles in the tumor microenvironment capable of affecting cell fate. Evidence demonstrates the existence of novel branches in the autophagy system related to cytoplasmic constituent’s secretion. Hence, autophagy-dependent secretion assembles a tangled network of signaling that potentially contributes to metabolism reprogramming, immune regulation, and tumor progression. Here, we summarize the current awareness regarding secretory autophagy and the intersection with exosome biogenesis and release in melanoma and their role in tumor resistance. In addition, we present and discuss data from public databases concerning autophagy and exosome-related genes as important mediators of melanoma behavior. Finally, we will present the main challenges in the field and strategies to translate most of the pre-clinical findings to clinical practice.

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Insights on autophagosome–lysosome tethering from structural and biochemical characterization of human autophagy factor EPG5

Cited by 13 publications

References 75 publications

Vici syndrome in Israel: Clinical and molecular insights

Vici syndrome in Israel: Clinical and molecular insights

Incomplete autophagy: Trouble is a friend

Secretory Autophagy Forges a Therapy Resistant Microenvironment in Melanoma

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