bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2021–09–05
eight papers selected by
Su Hyun Lee, Seoul National University
  1. Autophagy in major human diseases.
  2. LC3A-mediated autophagy regulates lung cancer cell plasticity.
  3. Autophagy in host stromal fibroblasts supports tumor desmoplasia.
  4. Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin condensate formation and autophagy initiation.
  5. Impairment of ULK1 sulfhydration-mediated lipophagy by SREBF1/SREBP-1c in hepatic steatosis.
  6. Ubiquitination of NF-κB p65 by FBXW2 suppresses breast cancer stemness, tumorigenesis, and paclitaxel resistance.
  7. Organelle-specific regulation of ferroptosis.
  8. USP21 Deubiquitinase Regulates AIM2 Inflammasome Activation.
  1. EMBO J. 2021 Aug 30. e108863
    Autophagy in major human diseases.
    Daniel J Klionsky, Giulia Petroni, Ravi K Amaravadi, Eric H Baehrecke, Andrea Ballabio, Patricia Boya, José Manuel Bravo-San Pedro, Ken Cadwell, Francesco Cecconi, Augustine M K Choi, Mary E Choi, Charleen T Chu, Patrice Codogno, Maria Isabel Colombo, Ana Maria Cuervo, Vojo Deretic, Ivan Dikic, Zvulun Elazar, Eeva-Liisa Eskelinen, Gian Maria Fimia, David A Gewirtz, Douglas R Green, Malene Hansen, Marja Jäättelä, Terje Johansen, Gábor Juhász, Vassiliki Karantza, Claudine Kraft, Guido Kroemer, Nicholas T Ktistakis, Sharad Kumar, Carlos Lopez-Otin, Kay F Macleod, Frank Madeo, Jennifer Martinez, Alicia Meléndez, Noboru Mizushima, Christian Münz, Josef M Penninger, Rushika M Perera, Mauro Piacentini, Fulvio Reggiori, David C Rubinsztein, Kevin M Ryan, Junichi Sadoshima, Laura Santambrogio, Luca Scorrano, Hans-Uwe Simon, Anna Katharina Simon, Anne Simonsen, Alexandra Stolz, Nektarios Tavernarakis, Sharon A Tooze, Tamotsu Yoshimori, Junying Yuan, Zhenyu Yue, Qing Zhong, Lorenzo Galluzzi, Federico Pietrocola.
      Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
    Keywords:  aging; cancer; inflammation; metabolic syndromes; neurodegeneration
    DOI:  https://doi.org/10.15252/embj.2021108863
  2. Autophagy. 2021 Sep 01. 1-14
    LC3A-mediated autophagy regulates lung cancer cell plasticity.
    Chia-Cheng Miao, Wen Hwang, Ling-Yi Chu, Li-Hao Yang, Cam-Thu Ha, Pei-Yu Chen, Ming-Han Kuo, Sheng-Chieh Lin, Ya-Yu Yang, Shuang-En Chuang, Chia-Cherng Yu, Shien-Tung Pan, Mou-Chieh Kao, Chuang-Rung Chang, Yu-Ting Chou.
       ABBREVIATIONS: ATG14: autophagy related 14; CDH2: cadherin 2; ChIP-qPCR: chromatin immunoprecipitation quantitative polymerase chain reaction; CQ: chloroquine; ECAR: extracellular acidification rate; EMT: epithelial-mesenchymal transition; EPCAM: epithelial cell adhesion molecule; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAP1LC3C/LC3C: microtubule associated protein 1 light chain 3 gamma; NDUFV2: NADH:ubiquinone oxidoreductase core subunit V2; OCR: oxygen consumption rate; ROS: reactive oxygen species; RT-qPCR: reverse-transcriptase quantitative polymerase chain reaction; SC: scrambled control; shRNA: short hairpin RNA; SNAI2: snail family transcriptional repressor 2; SOX2: SRY-box transcription factor 2; SQSTM1/p62: sequestosome 1; TGFB/TGF-β: transforming growth factor beta; TOMM20: translocase of outer mitochondrial membrane 20; ZEB1: zinc finger E-box binding homeobox 1.
    Keywords:  Autophagy; LC3A; SOX2; cancer cell plasticity; lung cancer; mitochondria dynamics
    DOI:  https://doi.org/10.1080/15548627.2021.1964224
  3. Autophagy. 2021 Sep 01. 1-2
    Autophagy in host stromal fibroblasts supports tumor desmoplasia.
    Jenny A Rudnick, Jayanta Debnath.
      Growing evidence demonstrates that macroautophagy/autophagy in the host stroma influences the tumor microenvironment. We have uncovered that autophagy in host stromal fibroblasts is compulsory to initiate and maintain the desmoplastic fibrotic response that fosters mammary tumor progression. Genetic loss of fibroblast autophagy impedes COL1A/type 1 collagen secretion, which is required for the development of a stiff tissue matrix permissive for mammary tumor growth. As a result, stromal fibroblast autophagy deficiency impairs mammary tumor progression in vivo, even when the cancer cells themselves remain autophagy competent. Our results provide unique conceptual insight into how the autophagy pathway can be modulated to abolish the desmoplastic response required for cancer progression.
    Keywords:  Autophagy; cancer associated fibroblasts; collagen; desmoplasia; tumor microenvironment
    DOI:  https://doi.org/10.1080/15548627.2021.1972405
  4. Nat Commun. 2021 Sep 01. 12(1): 5212
    Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin condensate formation and autophagy initiation.
    Eleonora Turco, Adriana Savova, Flora Gere, Luca Ferrari, Julia Romanov, Martina Schuschnig, Sascha Martens.
      The autophagic degradation of misfolded and ubiquitinated proteins is important for cellular homeostasis. In this process, which is governed by cargo receptors, ubiquitinated proteins are condensed into larger structures and subsequently become targets for the autophagy machinery. Here we employ in vitro reconstitution and cell biology to define the roles of the human cargo receptors p62/SQSTM1, NBR1 and TAX1BP1 in the selective autophagy of ubiquitinated substrates. We show that p62 is the major driver of ubiquitin condensate formation. NBR1 promotes condensate formation by equipping the p62-NBR1 heterooligomeric complex with a high-affinity UBA domain. Additionally, NBR1 recruits TAX1BP1 to the ubiquitin condensates formed by p62. While all three receptors interact with FIP200, TAX1BP1 is the main driver of FIP200 recruitment and thus the autophagic degradation of p62-ubiquitin condensates. In summary, our study defines the roles of all three receptors in the selective autophagy of ubiquitin condensates.
    DOI:  https://doi.org/10.1038/s41467-021-25572-w
  5. Autophagy. 2021 Aug 30. 1-2
    Impairment of ULK1 sulfhydration-mediated lipophagy by SREBF1/SREBP-1c in hepatic steatosis.
    Thuy T P Nguyen, Do-Young Kim, Seung-Soon Im, Tae-Il Jeon.
      Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the global population. However, its pathogenesis is not completely understood. In our recent study, we have demonstrated that in a high-fat diet-induced liver steatosis model, the activation of SREBF1/SREBP-1c (sterol regulatory element binding transcription factor 1) directly upregulates Mir216a transcription, which inhibits CTH/CSE (cystathionase (cystathionine gamma-lyase)) expression and its function in hydrogen sulfide (H2S) production. Reduced H2S production suppresses the sulfhydration of ULK1 (unc-51 like autophagy activating kinase 1), consequently inhibiting autophagic flux and lipid droplet turnover. A single substitution mutation (C951S) in ULK1 or the silencing of CTH impairs ULK1 sulfhydration-mediated lipophagy, thereby promoting hepatic steatosis in mice. Interestingly, the sulfhydration of ULK1 increases its intrinsic kinase activity to modulate autophagy at both initiation and progression stages of autophagic catabolic flux. This study reveals that SREBF1/SREBP-1c contributes to hepatic lipid accumulation through its combined effect of increased lipid synthesis coupled with decreased lipid degradation mediated by autophagic dysregulation.
    Keywords:  Autophagy; SREBP-1C; ULK1; hepatic steatosis; hydrogen sulfide; sulfhydration
    DOI:  https://doi.org/10.1080/15548627.2021.1968608
  6. Cell Death Differ. 2021 Aug 31.
    Ubiquitination of NF-κB p65 by FBXW2 suppresses breast cancer stemness, tumorigenesis, and paclitaxel resistance.
    Chune Ren, Xue Han, Chao Lu, Tingting Yang, Pengyun Qiao, Yonghong Sun, Zhenhai Yu.
      The F-box and WD-repeat-containing protein 2 (FBXW2) plays a crucial role as an E3 ligase in regulating tumorigenesis. However, the functions of FBXW2 in breast cancer are still unknown. Here, we find that nuclear factor-kB (NF-κB) p65 is a new substrate of FBXW2. FBXW2 directly binds to p65, leading to its ubiquitination and degradation. Interestingly, p300 acetylation of p65 blocks FBXW2 induced p65 ubiquitination. FBXW2-p65 axis is a crucial regulator of SOX2-induced stemness in breast cancer. Moreover, FBXW2 inhibits breast tumor growth by regulating p65 degradation in vitro and in vivo. FBXW2 overexpression abrogates the effects of p65 on paclitaxel resistance in vitro and in vivo. Furthermore, FBXW2 induced p65 degradation is also confirmed in FBXW2-knockout mice. Our results identify FBXW2 as an important E3 ligase for p65 degradation, which provide insights into the tumor suppressor functions of FBXW2 in breast cancer.
    DOI:  https://doi.org/10.1038/s41418-021-00862-4
  7. Cell Death Differ. 2021 Aug 31.
    Organelle-specific regulation of ferroptosis.
    Xin Chen, Rui Kang, Guido Kroemer, Daolin Tang.
      Ferroptosis, a cell death modality characterized by iron-dependent lipid peroxidation, is involved in the development of multiple pathological conditions, including ischemic tissue damage, infection, neurodegeneration, and cancer. The cellular machinery responsible for the execution of ferroptosis integrates multiple pro-survival or pro-death signals from subcellular organelles and then 'decides' whether to engage the lethal process or not. Here, we outline the evidence implicating different organelles (including mitochondria, lysosomes, endoplasmic reticulum, lipid droplets, peroxisomes, Golgi apparatus, and nucleus) in the ignition or avoidance of ferroptosis, while emphasizing their potential relevance for human disease and their targetability for pharmacological interventions.
    DOI:  https://doi.org/10.1038/s41418-021-00859-z
  8. J Immunol. 2021 Sep 01. pii: ji2100449. [Epub ahead of print]
    USP21 Deubiquitinase Regulates AIM2 Inflammasome Activation.
    Yujin Hong, Seong-Ok Lee, Changhoon Oh, Kwonyoon Kang, Jeongmin Ryoo, Dongyoung Kim, Kwangseog Ahn.
      Innate immune sensing of cytosolic DNA via absent in melanoma 2 (AIM2) is a key mechanism leading to inflammatory responses. As aberrant immune responses by dysregulated AIM2 are associated with autoinflammatory diseases, activation of the AIM2 inflammasome should be tightly controlled. In this study, we discovered that ubiquitination and deubiquitination of AIM2 are critical events that regulate AIM2 inflammasome activation. In resting human macrophage cells, AIM2 is constitutively ubiquitinated and undergoes proteasomal degradation to avoid autoinflammation. Upon DNA stimulation, USP21 binds to AIM2 and deubiquitinates it, thereby increasing its protein stability. In addition to the role of USP21 in regulating AIM2 turnover, we uncovered that USP21-mediated deubiquitination of AIM2 is required for the assembly of the AIM2 inflammasome. Depletion of USP21 does not affect the DNA-binding ability of AIM2 but inhibits the formation of the AIM2-ASC complex. Our findings establish that fine-tuning of AIM2 by the ubiquitin system is important for regulating AIM2 inflammasome activation.
    DOI:  https://doi.org/10.4049/jimmunol.2100449
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