The beclin 1 interactome: Modification and roles in the pathology of autophagy-related disorders

Kaur, Sargeet; Changotra, Harish

doi:10.1016/j.biochi.2020.04.025

Cited by 55 publications

(34 citation statements)

References 196 publications

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“…Undoubtedly, Beclin-1 dysfunction plays a central role in autophagy disorders. Thus, modulation of Beclin-1 significantly influences the stabilization of autophagy, thereby deeply affecting the cell survival and death [42,43]. As expected, our study further elucidated that the protective effects of miR-384-5p were connected with suppression of autophagy stress indicated by decreased levels of Beclin-1 in damaged lung tissues and reduced autophagosome formation in alveolar macrophages.…”

supporting

confidence: 77%

“…Beclin-1 is identified as a landmark protein of autophagy and crucial for the formation and maturation of autophagosomes. Many of these effects are mediated through the activation of specific Beclin-1 binding proteins, including autophagic inducers and autophagic inhibitors [42][43][44][45]. Undoubtedly, Beclin-1 dysfunction plays a central role in autophagy disorders.…”

mentioning

confidence: 99%

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BMSC-Derived Exosomes Ameliorate LPS-Induced Acute Lung Injury by miR-384-5p-Controlled Alveolar Macrophage Autophagy

Liu

Gao

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common critical diseases. Bone marrow mesenchymal stem cell (BMSC) transplantation is previously shown to effectively rescue injured lung tissues. The therapeutic mechanism of BMSC-derived exosomes is not fully understood. Here, we investigated the BMSC-derived exosomal microRNAs (miRNAs) on effecting lipopolysaccharide- (LPS-) induced ALI and its mechanism. In vitro, rat alveolar macrophages were treated with or without exosomes in the presence of 10 μg/ml LPS for 24 h. Cell viability was determined with Cell Counting Kit-8 assay. Apoptotic ratio was determined with TUNEL and Annexin V-FITC/PI double staining. The levels of miR-384-5p and autophagy-associated genes were measured by RT-qPCR and western blot. Autophagy was observed by TEM and assessed by means of the mRFP-GFP-LC3 adenovirus transfection assay. In vivo, we constructed LPS-induced ALI rat models. Exosomes were injected into rats via the caudal vein or trachea 4 h later after LPS treatment. The lung histological pathology was determined by H&E staining. Pulmonary vascular permeability was assessed by wet-to-dry weight ratio and Evans blue dye leakage assay, and inflammatory cytokines in serum and BALF were measured by ELISA. Furthermore, the therapeutic mechanism involved in miR-384-5p and Beclin-1 was determined. The results showed that BMSC-derived exosomes were taken up by the alveolar macrophages and attenuated LPS-induced alveolar macrophage viability loss and apoptosis. Exosomes effectively improved the survival rate of ALI rats within 7 days, which was associated with alleviating lung pathological changes and pulmonary vascular permeability and attenuating inflammatory response. Furthermore, this study for the first time found that miR-384-5p was enriched in BMSC-derived exosomes, and exosomal miR-384-5p resulted in relieving LPS-injured autophagy disorder in alveolar macrophages by targeting Beclin-1. Therefore, exosomal miR-384-5p could be demonstrated as a promising therapeutic strategy for ALI/ARDS.

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supporting

confidence: 77%

mentioning

confidence: 99%

BMSC-Derived Exosomes Ameliorate LPS-Induced Acute Lung Injury by miR-384-5p-Controlled Alveolar Macrophage Autophagy

Liu

Gao

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Furthermore, we found that a substantial fraction of ORF8 colocalized with Beclin 1, an essential protein for autophagy initiation to mediate autophagosome formation ( Fig. 5 H ) ( 36 , 37 ). Immunoprecipitation data further confirmed that ORF8 directly interacted with Beclin 1 ( Fig.…”

Section: Resultsmentioning

confidence: 86%

“…It is well known that Beclin 1 interacts with many regulatory proteins and acts as a scaffold to form multiprotein complex. In addition, Beclin 1 is a key player during autophagy initiation and nucleation ( 36 ). Although many proteins (i.e., HIV-1 Nef or the influenza virus matrix protein 2) interact with Beclin 1, leading to the blockade of autophagosome initiation, some Beclin 1–interacting proteins (i.e., Ambra1, Atg14L (Barkor), UVRAG, HMGB1, and Rubicon) induce the activation or maturation of autophagosomes ( 36 , 50 , 51 ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Beclin 1 is a key player during autophagy initiation and nucleation ( 36 ). Although many proteins (i.e., HIV-1 Nef or the influenza virus matrix protein 2) interact with Beclin 1, leading to the blockade of autophagosome initiation, some Beclin 1–interacting proteins (i.e., Ambra1, Atg14L (Barkor), UVRAG, HMGB1, and Rubicon) induce the activation or maturation of autophagosomes ( 36 , 50 , 51 ). Notably, ORF8 of SARS-CoV-2 is a unique example of pathogen-derived Beclin 1–binding protein that drives autophagy activation or maturation and further induces degradation of MHC-Ι of the host cells.…”

Section: Discussionmentioning

confidence: 99%

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The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-Ι

Zhang

Chen

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

331

332

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COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic and has claimed over 2 million lives worldwide. Although the genetic sequences of SARS-CoV and SARS-CoV-2 have high homology, the clinical and pathological characteristics of COVID-19 differ significantly from those of SARS. How and whether SARS-CoV-2 evades (cellular) immune surveillance requires further elucidation. In this study, we show that SARS-CoV-2 infection leads to major histocompability complex class Ι (MHC-Ι) down-regulation both in vitro and in vivo. The viral protein encoded by open reading frame 8 (ORF8) of SARS-CoV-2, which shares the least homology with SARS-CoV among all viral proteins, directly interacts with MHC-Ι molecules and mediates their down-regulation. In ORF8-expressing cells, MHC-Ι molecules are selectively targeted for lysosomal degradation via autophagy. Thus, SARS-CoV-2–infected cells are much less sensitive to lysis by cytotoxic T lymphocytes. Because ORF8 protein impairs the antigen presentation system, inhibition of ORF8 could be a strategy to improve immune surveillance.

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ATG5: A central autophagy regulator implicated in various human diseases

Changotra

Kaur

Yadav

et al. 2022

Cell Biochemistry & Function

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Autophagy, an intracellular conserved degradative process, plays a central role in the renewal/recycling of a cell to maintain the homeostasis of nutrients and energy within the cell. ATG5, a key component of autophagy, regulates the formation of the autophagosome, a hallmark of autophagy. ATG5 binds with ATG12 and ATG16L1 resulting in E3 like ligase complex, which is necessary for autophagosome expansion. Available data suggest that ATG5 is indispensable for autophagy and has an imperative role in several essential biological processes. Moreover, ATG5 has also been demonstrated to possess autophagy‐independent functions that magnify its significance and therapeutic potential. ATG5 interacts with various molecules for the execution of different processes implicated during physiological and pathological conditions. Furthermore, ATG5 genetic variants are associated with various ailments. This review discusses various autophagy‐dependent and autophagy‐independent roles of ATG5, highlights its various deleterious genetic variants reported until now, and various studies supporting it as a potential drug target.

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The beclin 1 interactome: Modification and roles in the pathology of autophagy-related disorders

Cited by 55 publications

References 196 publications

BMSC-Derived Exosomes Ameliorate LPS-Induced Acute Lung Injury by miR-384-5p-Controlled Alveolar Macrophage Autophagy

BMSC-Derived Exosomes Ameliorate LPS-Induced Acute Lung Injury by miR-384-5p-Controlled Alveolar Macrophage Autophagy

The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-Ι

ATG5: A central autophagy regulator implicated in various human diseases

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