bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2022‒05‒15
eight papers selected by
Su Hyun Lee
Seoul National University

  1. Autophagy. 2022 May 09.
      A recent screen of the Saccharomyces cerevisiae deletion library implicated End3 in autophagy of the endoplasmic reticulum (ER). Together with Pan1, End3 coordinates endocytic site initiation with the localized assembly of branching actin filaments that promotes invagination of endocytic pits. Oxysterol binding proteins function as an inter-organelle bridge by interacting with VAP proteins on the cortical ER and type I myosins on the endocytic pit. These proteins not only promote localized actin assembly at contact sites, they are required for ER autophagy as well. We propose that localized actin polymerization can push the edge of an ER sheet from the cell cortex towards the site of autophagosome assembly near the vacuole.
    Keywords:  Actin assembly; End3-Pan1; Myo3/Myo5; Osh2/Osh3; Scs2/Scs22; contact sites; endocytic pits; endoplasmic reticulum; reticulophagy
  2. EMBO J. 2022 May 13. e111424
      The lysosomal degradation pathway of autophagy depends on a set of evolutionarily conserved autophagy-related molecules (ATGs) bestowed with the power to direct membrane trafficking and biology. In this issue of EMBO Journal, Kakanj P et al reveal a surprising role for the autophagy machinery in cell fusion (Kakanj et al, 2022). Autophagy is physiologically required for cell syncytium formation through dismantling the lateral plasma membrane during wound healing, and unchecked autophagy can drive cell fusion in epithelial tissues without compromising epithelial integrity.
  3. FASEB J. 2022 May;36 Suppl 1
      Autophagy is a tightly controlled cellular recycling process that requires a host of autophagy machinery to form a double membraned vesicle called the autophagosome. This process is most understood in the context of stress-induced autophagy, with little known about autophagosome biogenesis in basal (nutrient replete) conditions. To understand the regulation of basal autophagy, our work has focused on the poorly understood protein ATG9A, a multi-pass transmembrane lipid scramblase that is essential for basal autophagy. To broadly understand the role ATG9A plays in basal autophagy, we utilized a quantitative proteome-level MS/MS approach to measure how ATG9A affects protein flux. We show that loss of ATG9A in basal conditions impairs the degradation of autophagy adaptors, particularly p62/SQSTM1. Using a panel of ATG knock-out cells, we demonstrate that the lipid transferase proteins ATG2A, ATG2B, and ATG9A promote the basal autophagic turnover of p62 and TAX1BP1 over other autophagy adaptors and do so independently of the LC3-lipidation machinery. Furthermore, we demonstrate that ATG2A and ATG9A lipid transferase activity regulates the rate of p62 condensate degradation. Finally, we show in CRISPR knock-in cell lines that ubiquitin is required for recruiting ATG9A to p62 condensates. Taken together, our data suggest that the lipid transferase activity of ATG9A and ATG2A is vital to basal autophagic regulation of protein homeostasis, and that ubiquitination is an apical signal that initiates recruitment of ATG9A to p62 condensates.
  4. Chem Biol Interact. 2022 May 09. pii: S0009-2797(22)00168-5. [Epub ahead of print] 109963
      4-Hydroxynonenal (4-HNE), the most toxic end-product of lipid peroxidation formed during oxidative stress, has been implicated in many diseases including neurodegenerative diseases, metabolic diseases, myocardial diseases, cancer and age-related diseases. 4-HNE can actively react with DNA, proteins and lipids, causing rapid cell death. The accumulation of 4-HNE leads to induction of autophagy, which clears damaged proteins and organelles. However, the underlying mechanism of 4-HNE-regulated autophagy is still not known. Transcriptional factor EB (TFEB) is a master regulator of lysosomal and autophagic functions, which we show here that TFEB is activated by 4-HNE. 4-HNE induces TFEB nuclear translocation and activated TFEB then upregulates the expression of genes required for autophagic and lysosomal biogenesis and function. Reactive oxygen species and Ca2+ are required in this process and TFEB activity is required for 4-HNE-mediated lysosomal function. Most importantly, genetic inhibition of TFEB (TFEB-KO) exacerbates 4-HNE-induced cell death, suggesting that TFEB is essential for cellular adaptive response to 4-HNE-induced cell damage. Hence, targeting TFEB to promote autophagic and lysosomal function may represent a promising approach to treat neurodegenerative and metabolic diseases in which 4-HNE accumulation has been implicated.
    Keywords:  4-Hydroxynonenal; Apoptosis; Lysosome; ROS; TFEB
  5. J Hematol Oncol. 2022 May 07. 15(1): 51
      Acute myeloid leukemia (AML) is a severe hematologic malignancy prevalent in older patients, and the identification of potential therapeutic targets for AML is problematic. Autophagy is a lysosome-dependent catabolic pathway involved in the tumorigenesis and/or treatment of various cancers. Mounting evidence has suggested that autophagy plays a critical role in the initiation and progression of AML and anticancer responses. In this review, we describe recent updates on the multifaceted functions of autophagy linking to genetic alterations of AML. We also summarize the latest evidence for autophagy-related genes as potential prognostic predictors and drivers of AML tumorigenesis. We then discuss the crosstalk between autophagy and tumor cell metabolism into the impact on both AML progression and anti-leukemic treatment. Moreover, a series of autophagy regulators, i.e., the inhibitors and activators, are described as potential therapeutics for AML. Finally, we describe the translation of autophagy-modulating therapeutics into clinical practice. Autophagy in AML is a double-edged sword, necessitating a deeper understanding of how autophagy influences dual functions in AML tumorigenesis and anti-leukemic responses.
    Keywords:  Acute myeloid leukemia; Apoptosis; Autophagy; Therapeutics
  6. FASEB J. 2022 May;36 Suppl 1
      The covalent attachment of ubiquitin to substrates controls virtually all aspects of the cell. With rare exceptions, ubiquitin was understood to exert its effects by becoming attached to the amino group of lysine residues within protein substrates. Recent discoveries from our lab and others have revealed that dedicated writers (E3 ligases) and erasers (DUBs) of non-lysine ubiquitination are intrinsic to eukaryotes. This highlights that attachment to sites beyond lysine are physiologically and perhaps pathologically important. These E3s tend to be highly divergent from their established counterparts and "activity-based" chemical biology approaches have been instrumental in identifying them. I will present work from my lab on technologies we have used to uncover unusual E3 ligases and the striking nature of their mechanism and substrate specificity. I will also discuss our characterisation of a small DUB family that is highly selective at removing ubiquitin from hydroxy amino acids. These new developments indicate that non-lysine ubiquitination is an integral component of the ubiquitin system that is subject to sophisticated regulation.
  7. Autophagy. 2022 May 09. 1-2
      Resistance to chemo-immunotherapy is a major issue for the treatment of non-small cell lung cancer. In a recent paper we unravel the role of MAPK in the capacity of restraining the therapeutic efficacy of chemo-immunotherapy. Inhibition of the MAPK pathway using a MAP2K/MEK inhibitor in combination with chemotherapy could promote OPTN (optineurin)-dependent mitophagy of cancer cells. Mitochondria then degrade via autophagosomes and amphisomes and release mitochondrial DNA, which interacts with TLR9 located in these compartments. TLR9 activation promotes the production of the chemokine CXCL10 by cancer cells, which could further improve T cell recruitment and improve the efficacy of immunotherapy.
    Keywords:  CXCL10; Chemotherapy; MAP2K/MEK inhibitor; TLR9; ULK1; immunotherapy; mitophagy; optineurin
  8. Autophagy. 2022 May 09. 1-2
      The unique cellular organization and metabolic demands of neurons pose a challenge in the maintenance of neuronal homeostasis. A critical element in maintaining neuronal health and homeostasis is mitochondrial quality control via replacement and rejuvenation at the axon. Dysregulation of mitochondrial quality control mechanisms such as mitophagy has been implicated in neurodegenerative diseases including Parkinson disease and amyotrophic lateral sclerosis. To sustain mitophagy at the axon, a continuous supply of PINK1 is required; however, how do neurons maintain a steady supply of this protein at the distal axons? In the study highlighted here, Harbauer et al. show that axonal mitophagy is supported by local translation of Pink1 mRNA that is co-transported with mitochondria to the distal ends of the neuron. This neuronal-specific pathway provides a continuous supply of PINK1 to sustain mitophagy.
    Keywords:  Autophagy; mitochondria; neurodegeneration; neuron; stress