Autophagy is a primarily degradative pathway that takes place in all eukaryotic cells. It is used for recycling cytoplasm to generate macromolecular building blocks and energy under stress conditions, to remove superfluous and damaged organelles to adapt to changing nutrient conditions and to maintain cellular homeostasis. In addition, autophagy plays a critical role in cytoprotection by preventing the accumulation of toxic proteins and through its action in various aspects of immunity including the elimination of invasive microbes and its participation in antigen presentation. The most prevalent form of autophagy is macroautophagy, and during this process, the cell forms a double-membrane sequestering compartment termed the phagophore, which matures into an autophagosome. Following delivery to the vacuole or lysosome, the cargo is degraded and the resulting macromolecules are released back into the cytosol for reuse. The past two decades have resulted in a tremendous increase with regard to the molecular studies of autophagy being carried out in yeast and other eukaryotes. Part of the surge in interest in this topic is due to the connection of autophagy with a wide range of human pathophysiologies including cancer, myopathies, diabetes and neurodegenerative disease. However, there are still many aspects of autophagy that remain unclear, including the process of phagophore formation, the regulatory mechanisms that control its induction and the function of most of the autophagy-related proteins. In this review, we focus on macroautophagy, briefly describing the discovery of this process in mammalian cells, discussing the current views concerning the donor membrane that forms the phagophore, and characterizing the autophagy machinery including the available structural information.
Macroautophagy (hereafter autophagy), literally defined as a type of self-eating, is a dynamic cellular process in which cytoplasm is sequestered within a unique compartment termed the phagophore. Upon completion, the phagophore matures into a double-membrane autophagosome that fuses with the lysosome or vacuole, allowing degradation of the cargo. Nonselective autophagy is primarily a cytoprotective response to various types of stress; however, the process can also be highly selective. Autophagy is involved in various aspects of cell physiology, and its dysregulation is associated with a range of diseases. The regulation of autophagy is complex, and the process must be properly modulated to maintain cellular homeostasis. In this review, we focus on the current state of knowledge concerning transcriptional, post-transcriptional, and post-translational regulation of autophagy in yeast and mammals.
Airway eosinophilic inflammation is a key feature of type 2 high asthma. The role of epithelial microRNA (miR) in airway eosinophilic inflammation remains unclear. We examined the expression of miR-221-3p in bronchial brushings, induced sputum, and plasma from 77 symptomatic, recently diagnosed, steroid-naive subjects with asthma and 36 healthy controls by quantitative PCR and analyzed the correlation between miR-221-3p expression and airway eosinophilia. We found that epithelial, sputum, and plasma miR-221-3p expression was significantly decreased in subjects with asthma. Epithelial miR-221-3p correlated with eosinophil in induced sputum and bronchial biopsies, fraction of exhaled nitric oxide, blood eosinophil, epithelial gene signature of type 2 status, and methacholine provocative dosage required to cause a 20% decline in forced expiratory volume in the first second in subjects with asthma. Sputum miR-221-3p also correlated with airway eosinophilia and was partially restored after inhaled corticosteroid treatment. Inhibition of miR-221-3p expression suppressed chemokine (C-C motif) ligand (CCL) 24 (eotaxin-2), CCL26 (eotaxin-3), and periostin (POSTN) expression in BEAS-2B bronchial epithelial cells. We verified that chemokine (C-X-C motif) ligand (CXCL) 17, an anti-inflammatory chemokine, is a target of miR-221-3p, and epithelial CXCL17 expression significantly increased in asthma. CXCL17 inhibited CCL24, CCL26, and POSTN expression via the p38 MAPK pathway. Airway overexpression of miR-221-3p exacerbated airway eosinophilic inflammation, suppressed CXCL17 expression, and enhanced CCL24, CCL26, and POSTN expression in house dust mite-challenged mice. Taken together, epithelial and sputum miR-221-3p are novel biomarkers for airway eosinophilic inflammation in asthma. Decreased epithelial miR-221-3p may protect against airway eosinophilic inflammation by upregulating anti-inflammatory chemokine CXCL17.
Background: Older age and elevated d-dimer are reported risk factors for coronavirus disease 2019 (COVID-19). However, whether early radiographic change is a predictor of fatality remains unknown. Methods: We retrospectively reviewed records of all laboratory-confirmed patients admitted to a quarantine unit at Tongji Hospital, a large regional hospital in Wuhan, China, between January 31 and March 5, 2020. Confirmed cases were defined by positive RT-PCR detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in throat-swab specimens. Chest CT images were reviewed independently by two radiologists. The Tongji Hospital ethics committee approved this study. Results: A total of 102 patients were confirmed to have SARS-CoV-2 infection. As of March 25, 85 confirmed patients were discharged, 15 died, and 2 remained hospitalized. When compared with survivors, non-survivors were older (median age, 69 [interquartile range, 58-77] vs. 55 [44-66], p = 0.003), and more likely to have decreased lymphocyte count (0.5 vs. 0.9 × 10 9 /L, p = 0.006), elevated lactate dehydrogenase (LDH) (569.0 vs. 272.0 U/L, p < 0.001), elevated d-dimer (> 1 μg/mL, 86% vs. 37%, p = 0.002) on admission. Older age and elevated LDH were independent risk factors for fatality in a multivariate regression model included the above variables. In a subset of patients with CT images within the first week, higher total severity score, and more involved lung lobes (5 involved lobes) in CT images within the first week were significantly associated with fatality. Moreover, in this subset of patients, higher total severity score was the only independent risk factor in a multivariate analysis incorporating the above mentioned variables. Conclusions: Older age, elevated LDH on admission, and higher severity score of CT images within the first week are potential predictors of fatality in adults with COVID-19. These predictors may help clinicians identify patients with a poor prognosis at an early stage.
Macroautophagy is primarily a degradative process that cells use to break down their own components to recycle macromolecules and provide energy under stress conditions, and defects in macroautophagy lead to a wide range of diseases. Atg9, conserved from yeast to mammals, is the only identified transmembrane protein in the yeast core macroautophagy machinery required for formation of the sequestering compartment termed the autophagosome. This protein undergoes dynamic movement between the phagophore assembly site (PAS), where the autophagosome precursor is nucleated, and peripheral sites that may provide donor membrane for expansion of the phagophore. Atg9 is a phosphoprotein that is regulated by the Atg1 kinase. We used stable isotope labeling by amino acids in cell culture (SILAC) to identify phosphorylation sites on this protein and identified an Atg1-independent phosphorylation site at serine 122. A nonphosphorylatable Atg9 mutant showed decreased autophagy activity, whereas the phosphomimetic mutant enhanced activity. Electron microscopy analysis suggests that the different levels of autophagy activity reflect differences in autophagosome formation, correlating with the delivery of Atg9 to the PAS. Finally, this phosphorylation regulates Atg9 interaction with Atg23 and Atg27.
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