Autophagy: The spotlight for cellular stress responses.

The MiT-TFE family of basic helix-loop-helix leucine-zipper transcription factors includes four members: TFEB, TFE3, TFEC, and MITF Originally described as oncogenes, these factors play a major role as regulators of lysosome biogenesis, cellular energy homeostasis, and autophagy. An important mechanism by which these transcription factors are regulated involves their shuttling between the surface of lysosomes, the cytoplasm, and the nucleus. Such dynamic changes in subcellular localization occur in response to nutrient fluctuations and various forms of cell stress and are mediated by changes in the phosphorylation of multiple conserved amino acids. Major kinases responsible for MiT-TFE protein phosphorylation include mTOR, ERK, GSK3, and AKT In addition, calcineurin de-phosphorylates MiT-TFE proteins in response to lysosomal calcium release. Thus, through changes in the phosphorylation state of MiT-TFE proteins, lysosome function is coordinated with the cellular metabolic state and cellular demands. This review summarizes the evidence supporting MiT-TFE regulation by phosphorylation at multiple key sites. Elucidation of such regulatory mechanisms is of fundamental importance to understand how these transcription factors contribute to both health and disease.

https://www.embopress.org/doi/pdf/10.15252/embj.201798804

The complex relationship between TFEB transcription factor phosphorylation and subcellular localization.

Therapeutic Targeting of Autophagy.

Cells rely on surveillance systems such as autophagy to handle protein alterations and organelle damage. Dysfunctional autophagy, an evolutionarily conserved cellular mechanism for degradation of intracellular components in lysosomes, frequently leads to neurodegeneration. The neuroprotective effect of autophagy stems from its ability to eliminate pathogenic forms of proteins such as α-synuclein or tau. However, the same pathogenic proteins often affect different types and steps of the autophagic process. Furthermore, genetic studies have shown that some proteins related to neurodegeneration, such as huntingtin, participate in autophagy as one of their physiological functions. This complex interplay between autophagy and neurodegeneration suggests that targeting autophagy as a whole might have limited applicability in neurodegenerative diseases, and that future efforts should focus instead on targeting specific types and steps of the autophagic process. This change of strategy in the modulation of autophagy might hold promise for future disease-modifying therapies for patients with neurodegenerative disorders.

Selective autophagy as a potential therapeutic target for neurodegenerative disorders.

The molecular mechanisms underlying the severe lung pathology that occurs during SARS-CoV infections remain incompletely understood The largest of the SARS-CoV accessory protein open reading frames (SARS 3a) oligomerizes, dynamically inserting into late endosomal, lysosomal, and trans-Golgi-network membranes While previously implicated in a non-inflammatory apoptotic cell death pathway, here we extend the range of SARS 3a pathophysiologic targets by examining its effects on necrotic cell death pathways We show that SARS 3a interacts with Receptor Interacting Protein 3 (Rip3), which augments the oligomerization of SARS 3a helping drive necrotic cell death In addition, by inserting into lysosomal membranes SARS 3a triggers lysosomal damage and dysfunction Consequently, Transcription Factor EB (TFEB) translocates to the nucleus increasing the transcription of autophagy- and lysosome-related genes Finally, SARS 3a activates caspase-1 either directly or via an enhanced potassium efflux, which triggers NLRP3 inflammasome assembly In summary, Rip3-mediated oligomerization of SARS 3a causes necrotic cell death, lysosomal damage, and caspase-1 activation—all likely contributing to the clinical manifestations of SARS-CoV infection

/pdf/sars-coronavirus-open-reading-frame-3a-drives-multimodal-33e1drd8qk.pdf

Yueru Sun

Papers

High-efficiency removal of antibiotic pollutants by magnetic carbon aerogel: Inherent roles of adsorption synergistic catalysis

All-in-one strategy to prepare molded biochar with magnetism from sewage sludge for high-efficiency removal of Cd(Ⅱ).