bims-apauto 2022-06-05 papers

bims-apauto

Biomed News

on Apoptosis and autophagy

Issue of 2022–06–05
eight papers selected by
Su Hyun Lee, Seoul National University

The fate of autophagosomal membrane components.
A prion-like domain of TFEB mediates the co-aggregation of TFEB and mHTT.
Programmed Cell Death in Sepsis Associated Acute Kidney Injury.
Crosstalk Between Autophagy and Innate Immunity: A Pivotal Role in Hepatic Fibrosis.
Stress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate.
Glycogen-autophagy: Molecular machinery and cellular mechanisms of glycophagy.
Non-canonical mTORC1 signaling at the lysosome.
Macrophages disseminate pathogen associated molecular patterns through the direct extracellular release of the soluble content of their phagolysosomes.

Autophagy. 2022 Jun 02. 1-2

The fate of autophagosomal membrane components.

Zhe Wu, Chuchu Zhou, Huilin Que, Yufen Wang, Yueguang Rong.

  During macroautophagy/autophagy, autophagosomes fuse with lysosomes to form autolysosomes. After fusion, the autophagosome inner membrane and enclosed substrates are degraded and transported out of lysosomes for recycling. The lysosomal membrane components are recycled by autophagic lysosome reformation (ALR) to generate new lysosomes. However, the fate of autophagosome outer membrane components on autolysosomes remains unknown. Our recent work discovered that autophagosome outer membrane components are not degraded but are recycled through an unidentified process which we named autophagosomal components recycling (ACR). Further investigation revealed the recycler complex (SNX4-SNX5-SNX17) responsible for ACR. The discovery of ACR not only fills a missing part in autophagy, but also reveals a new recycling pathway on autolysosomes.

Keywords:  ATG9A; STX17; autophagosomal components recycling; autophagy; lysosome

DOI:  https://doi.org/10.1080/15548627.2022.2083807
Autophagy. 2022 Jun 01. 1-7

A prion-like domain of TFEB mediates the co-aggregation of TFEB and mHTT.

Junsheng Yang, Huilin Xu, Chaoyue Zhang, Xiaotong Yang, Weijie Cai, Xiaoli Chen.

  The aggregation of mutant HTT (huntingtin; mHTT) is a hallmark of Huntington disease (HD). mHTT aggregates interact and sequester dozens of proteins and affect diverse key cellular functions. Here we report that TFEB (transcription factor EB), a master regulator of lysosome biogenesis and autophagy, is yet another protein that co-aggregates with mHTT. We also found the mHTT-TFEB co-aggregation is mediated by a prion-like domain (PrLD) near the N terminus of TFEB. Our findings point out a possible limitation for therapeutic strategies targeting TFEB to clear mHTT, and also provided a possible explanation for controversies that TFEB overexpression lowered soluble mHTT in some HD models but failed to reduce mHTT aggregates or HD pathology in others. Moreover, we found that TFE3, another MiT family transcription factor that shares overlapping functions with TFEB, lacks PrLD and does not co-aggregate with mHTT, and thus might serve as an alternative drug target for HD.

Keywords:  Aggregate; HD; TFEB; mHTT; prion-like domain

DOI:  https://doi.org/10.1080/15548627.2022.2083857
Front Med (Lausanne). 2022 ;9 883028

Programmed Cell Death in Sepsis Associated Acute Kidney Injury.

Zhifen Wu, Junhui Deng, Hongwen Zhou, Wei Tan, Lirong Lin, Jurong Yang.

  Sepsis-associated acute kidney injury (SA-AKI) is common in patients with severe sepsis, and has a high incidence rate and high mortality rate in ICU patients. Most patients progress to AKI before drug treatment is initiated. Early studies suggest that the main mechanism of SA-AKI is that sepsis leads to vasodilation, hypotension and shock, resulting in insufficient renal blood perfusion, finally leading to renal tubular cell ischemia and necrosis. Research results in recent years have shown that programmed cell death such as apoptosis, necroptosis, pyroptosis and autophagy play important roles. In the early stage of sepsis-related AKI, autophagy bodies form and inhibit various types of programmed cell death. With the progress of disease, programmed cell death begins. Apoptosis promoter represents caspase-8-induced apoptosis and apoptosis effector represents caspase-3-induced apoptosis, however, caspase-11 and caspase-1 regulate gasdermin D-mediated pyroptosis. Caspase-8 and receptor interacting kinase 1 bodies mediate necroptosis. This review focuses on the pathophysiological mechanisms of various programmed cell death in sepsis-related AKI.

Keywords:  acute kidney injury; apoptosis; autophagy; necroptosis; pyroptosis; sepsis; sepsis-associated acute kidney injury

DOI:  https://doi.org/10.3389/fmed.2022.883028
Front Pharmacol. 2022 ;13 891069

Crosstalk Between Autophagy and Innate Immunity: A Pivotal Role in Hepatic Fibrosis.

Li Chen, Desong Kong, Siwei Xia, Feixia Wang, Zhanghao Li, Feng Zhang, Shizhong Zheng.

  Liver fibrosis is a repair process of chronic liver injuries induced by toxic substances, pathogens, and inflammation, which exhibits a feature such as deposition of the extracellular matrix. The initiation and progression of liver fibrosis heavily relies on excessive activation of hepatic stellate cells (HSCs). The activated HSCs express different kinds of chemokine receptors to further promote matrix remodulation. The long-term progression of liver fibrosis will contribute to dysfunction of the liver and ultimately cause hepatocellular carcinoma. The liver also has abundant innate immune cells, including DCs, NK cells, NKT cells, neutrophils, and Kupffer cells, which conduct complicated functions to activation and expansion of HSCs and liver fibrosis. Autophagy is one specific type of cell death, by which the aberrantly expressed protein and damaged organelles are transferred to lysosomes for further degradation, playing a crucial role in cellular homeostasis. Autophagy is also important to innate immune cells in various aspects. The previous studies have shown that dysfunction of autophagy in hepatic immune cells can result in the initiation and progression of inflammation in the liver, directly or indirectly causing activation of HSCs, which ultimately accelerate liver fibrosis. Given the crosstalk between innate immune cells, autophagy, and fibrosis progression is complicated, and the therapeutic options for liver fibrosis are quite limited, the exploration is essential. Herein, we review the previous studies about the influence of autophagy and innate immunity on liver fibrosis and the molecular mechanism to provide novel insight into the prevention and treatment of liver fibrosis.

Keywords:  HSCs; autophagy; immune cells; innate immunity; liver fibrosis

DOI:  https://doi.org/10.3389/fphar.2022.891069
Nat Commun. 2022 Jun 02. 13(1): 3074

Stress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate.

Daniel C Carrettiero, Maria C Almeida, Andrew P Longhini, Jennifer N Rauch, Dasol Han, Xuemei Zhang, Saeed Najafi, Jason E Gestwicki, Kenneth S Kosik.

The formation of membraneless organelles can be a proteotoxic stress control mechanism that locally condenses a set of components capable of mediating protein degradation decisions. The breadth of mechanisms by which cells respond to stressors and form specific functional types of membraneless organelles, is incompletely understood. We found that Bcl2-associated athanogene 2 (BAG2) marks a distinct phase-separated membraneless organelle, triggered by several forms of stress, particularly hyper-osmotic stress. Distinct from well-known condensates such as stress granules and processing bodies, BAG2-containing granules lack RNA, lack ubiquitin and promote client degradation in a ubiquitin-independent manner via the 20S proteasome. These organelles protect the viability of cells from stress and can traffic to the client protein, in the case of Tau protein, on the microtubule. Components of these ubiquitin-independent degradation organelles include the chaperone HSP-70 and the 20S proteasome activated by members of the PA28 (PMSE) family. BAG2 condensates did not co-localize with LAMP-1 or p62/SQSTM1. When the proteasome is inhibited, BAG2 condensates and the autophagy markers traffic to an aggresome-like structure.

DOI: https://doi.org/10.1038/s41467-022-30751-4
J Biol Chem. 2022 May 30. pii: S0021-9258(22)00534-8. [Epub ahead of print] 102093

Glycogen-autophagy: Molecular machinery and cellular mechanisms of glycophagy.

Parisa Koutsifeli, Upasna Varma, Lorna J Daniels, Marco Annandale, Xun Li, Joshua P H Neale, Sarah Hayes, Kate L Weeks, Samuel James, Lea M D Delbridge, Kimberley M Mellor.

  Autophagy is an essential cellular process involving degradation of superfluous or defective macromolecules and organelles as a form of homeostatic recycling. Initially proposed to be a 'bulk' degradation pathway, a more nuanced appreciation of selective autophagy pathways has developed in the literature in recent years. As a glycogen-selective autophagy process, 'glycophagy' is emerging as a key metabolic route of transport and delivery of glycolytic fuel substrate. Study of glycophagy is at an early stage. Enhanced understanding of this major non-canonical pathway of glycogen flux will provide important opportunities for new insights into cellular energy metabolism. In addition, glycogen metabolic mishandling is centrally involved in the pathophysiology of several metabolic diseases in a wide range of tissues, including liver, skeletal muscle, cardiac muscle, and brain. Thus, advances in this exciting new field are of broad multi-disciplinary interest relevant to many cell types and metabolic states. Here, we review the current evidence of glycophagy involvement in homeostatic cellular metabolic processes and of molecular mediators participating in glycophagy flux, We integrate information from a variety of settings including cell lines, primary cell culture systems, ex vivo tissue preparations, genetic disease models and clinical glycogen disease states.

Keywords:  Atg8; Gabarapl1; Stbd1; autophagy; glycogen; glycophagy; lysosome

DOI:  https://doi.org/10.1016/j.jbc.2022.102093
Trends Cell Biol. 2022 May 30. pii: S0962-8924(22)00117-9. [Epub ahead of print]

Non-canonical mTORC1 signaling at the lysosome.

Gennaro Napolitano, Chiara Di Malta, Andrea Ballabio.

  The mechanistic target of rapamycin complex 1 (mTORC1) signaling hub integrates multiple environmental cues to modulate cell growth and metabolism. Over the past decade considerable knowledge has been gained on the mechanisms modulating mTORC1 lysosomal recruitment and activation. However, whether and how mTORC1 is able to elicit selective responses to diverse signals has remained elusive until recently. We discuss emerging evidence for a 'non-canonical' mTORC1 signaling pathway that controls the function of microphthalmia/transcription factor E (MiT-TFE) transcription factors, key regulators of cell metabolism. This signaling pathway is mediated by a specific mechanism of substrate recruitment, and responds to stimuli that appear to converge on the lysosomal surface. We discuss the relevance of this pathway in physiological and disease conditions.

Keywords:  FLCN; Rag GTPases; TFEB; lysosome; mTORC1

DOI:  https://doi.org/10.1016/j.tcb.2022.04.012
Nat Commun. 2022 Jun 02. 13(1): 3072

Macrophages disseminate pathogen associated molecular patterns through the direct extracellular release of the soluble content of their phagolysosomes.

Catherine J Greene, Jenny A Nguyen, Samuel M Cheung, Corey R Arnold, Dale R Balce, Ya Ting Wang, Adrian Soderholm, Neil McKenna, Devin Aggarwal, Rhiannon I Campden, Benjamin W Ewanchuk, Herbert W Virgin, Robin M Yates.

Recognition of pathogen-or-damage-associated molecular patterns is critical to inflammation. However, most pathogen-or-damage-associated molecular patterns exist within intact microbes/cells and are typically part of non-diffusible, stable macromolecules that are not optimally immunostimulatory or available for immune detection. Partial digestion of microbes/cells following phagocytosis potentially generates new diffusible pathogen-or-damage-associated molecular patterns, however, our current understanding of phagosomal biology would have these molecules sequestered and destroyed within phagolysosomes. Here, we show the controlled release of partially-digested, soluble material from phagolysosomes of macrophages through transient, iterative fusion-fission events between mature phagolysosomes and the plasma membrane, a process we term eructophagy. Eructophagy is most active in proinflammatory macrophages and further induced by toll like receptor engagement. Eructophagy is mediated by genes encoding proteins required for autophagy and can activate vicinal cells by release of phagolysosomally-processed, partially-digested pathogen associated molecular patterns. We propose that eructophagy allows macrophages to amplify local inflammation through the processing and dissemination of pathogen-or-damage-associated molecular patterns.

DOI: https://doi.org/10.1038/s41467-022-30654-4