bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2022‒03‒27
eleven papers selected by
Su Hyun Lee
Seoul National University
  1. Palmitoylation facilitates inflammation through suppressing NOD2 degradation mediated by the selective autophagy receptor SQSTM1.
  2. TFEB- and TFE3-dependent autophagy activation supports cancer proliferation in the absence of centrosomes.
  3. ATG16L1 WD40 domain-dependent IL10R (interleukin 10 receptor) signaling is insensitive to the T300A Crohn disease risk polymorphism.
  4. The TRIM14-USP14-BRCC3 complex epigenetically regulates inflammation through inhibiting OPTN-mediated autophagic degradation of KDM4D.
  5. Outer membrane vesicles produced by pathogenic strains of Escherichia coli block autophagic flux and exacerbate inflammasome activation.
  6. Nobiletin as an inducer of programmed cell death in cancer: a review.
  7. Oncogenic viral infection and amino acid metabolism in cancer progression: Molecular insights and clinical implications.
  8. Activation of lysosomal mediated cell death in the course of autophagy by mTORC1 inhibitor.
  9. S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions.
  10. Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer.
  11. PUMILIO proteins promote colorectal cancer growth via suppressing p21.
  1. Autophagy. 2022 Mar 24. 1-2
    Palmitoylation facilitates inflammation through suppressing NOD2 degradation mediated by the selective autophagy receptor SQSTM1.
    Lingli Zhou, Huasong Zeng, Jun Cui, Shouheng Jin.
      The intracellular pattern recognition receptor NOD2 senses bacterial peptidoglycan to drive proinflammatory and antimicrobial responses. Dysregulation of NOD2 signaling confers susceptibility to several immunological and inflammatory diseases. Although palmitoylation of NOD2 is required for its membrane recruitment and activation, whether palmitoylation can modulate the stability of NOD2 to orchestrate inflammation remains unclear. Recently, we have revealed that S-palmitoylation restricts SQSTM1-mediated selective macroautophagic/autophagic degradation of NOD2, and identified a gain-of-function R444C variant of NOD2 short isoform (NOD2sR444C) in autoinflammatory disease, which induces excessive inflammation through its enhanced S-palmitoylation level and decreased autophagic degradation.
    Keywords:  Inflammation; NOD2; S-palmitoylation; SQSTM1; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2054041
  2. Autophagy. 2022 Mar 22. 1-21
    TFEB- and TFE3-dependent autophagy activation supports cancer proliferation in the absence of centrosomes.
    Chien-Han Kao, Ting-Yu Su, Wei-Syun Huang, Xin-Ying Lu, Wann-Neng Jane, Chien-Yung Huang, Hung-Hsiang Huang, Won-Jing Wang.
      Centrosome amplification is a phenomenon frequently observed in human cancers, so centrosome depletion has been proposed as a therapeutic strategy. However, despite being afflicted with a lack of centrosomes, many cancer cells can still proliferate, implying there are impediments to adopting centrosome depletion as a treatment strategy. Here, we show that TFEB- and TFE3-dependent autophagy activation contributes to acentrosomal cancer proliferation. Our biochemical analyses uncover that both TFEB and TFE3 are novel PLK4 (polo like kinase 4) substrates. Centrosome depletion inactivates PLK4, resulting in TFEB and TFE3 dephosphorylation and subsequent promotion of TFEB and TFE3 nuclear translocation and transcriptional activation of autophagy- and lysosome-related genes. A combination of centrosome depletion and inhibition of the TFEB-TFE3 autophagy-lysosome pathway induced strongly anti-proliferative effects in cancer cells. Thus, our findings point to a new strategy for combating cancer.
    Keywords:  Anti-cancer therapy; PLK4; autophagy; centrosome; lysosomal biogenesis; transcription factor E3; transcription factor EB
    DOI:  https://doi.org/10.1080/15548627.2022.2051880
  3. Autophagy. 2022 Mar 20.
    ATG16L1 WD40 domain-dependent IL10R (interleukin 10 receptor) signaling is insensitive to the T300A Crohn disease risk polymorphism.
    Inmaculada Serramito-Gómez, Elena Terraza-Silvestre, Álvaro Fernández-Cabrera, Raquel Villamuera, Felipe X Pimentel-Muiños.
      A coding allele of ATG16L1 that increases the risk of Crohn disease (T300A; rs2241880) impairs the interaction between the C-terminal WD40 domain (WDD) and proteins containing a WDD-binding motif, thus specifically inhibiting the unconventional autophagic activities of ATG16L1. In a recent publication we described a novel atypical role of ATG16L1 in the regulation of IL10R (interleukin 10 receptor) trafficking and signaling, an activity that involves direct interaction between the WDD and a target motif present in IL10RB (interleukin 10 receptor subunit beta). Here we show that, unexpectedly, neither the ability of ATG16L1 to interact with IL10RB nor its role in supporting IL10 signaling are altered by the T300A mutation. These results indicate that the ATG16L1T300A allele selectively impairs the interaction between the WDD and a subset of WDD-binding motif versions, suggesting that only a fraction of the unconventional activities mediated by ATG16L1 are required to prevent Crohn disease.
    Keywords:  ATG16L1; Crohn disease; T300A allele; WD40 domain; cytokine signaling; unconventional autophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2054241
  4. Autophagy. 2022 Mar 23. 1-2
    The TRIM14-USP14-BRCC3 complex epigenetically regulates inflammation through inhibiting OPTN-mediated autophagic degradation of KDM4D.
    Di Liu, Shouheng Jin, Jun Cui.
      Macroautophagy/autophagy is a conserved eukaryotic process to mediate the degradation of cell organelles and protein aggregates, which participates in a variety of cellular responses, including immune signal transduction. KDM4D functions as an important histone demethylase to regulate gene transcription by inhibiting histone H3K9 trimethylation. Whether autophagy epigenetically regulates the immune response via modulating the stability and activity of KDM4D remains largely unclear. Recently, we identified TRIM14 (tripartite motif-containing 14) as an epigenetic regulator, which recruits USP14 and BRCC3 to form a regulatory complex, and promotes an inflammation response through inhibiting OPTN-mediated autophagic degradation of KDM4D.
    Keywords:  Autophagy; KDM4D; TRIM14; epigenetic regulation; inflammation
    DOI:  https://doi.org/10.1080/15548627.2022.2055286
  5. Autophagy. 2022 Mar 20.
    Outer membrane vesicles produced by pathogenic strains of Escherichia coli block autophagic flux and exacerbate inflammasome activation.
    Laure David, Frédéric Taieb, Marie Pénary, Pierre-Jean Bordignon, Rémi Planès, Salimata Bagayoko, Valérie Duplan-Eche, Etienne Meunier, Eric Oswald.
      Escherichia coli strains are responsible for a majority of human extra-intestinal infections, resulting in huge direct medical and social costs. We had previously shown that HlyF encoded by a large virulence plasmid harbored by pathogenic E. coli is not a hemolysin but a cytoplasmic enzyme leading to the overproduction of outer membrane vesicles (OMVs). Here, we showed that these specific OMVs inhibit the macroautophagic/autophagic flux by impairing the autophagosome-lysosome fusion, thus preventing the formation of acidic autolysosomes and autophagosome clearance. Furthermore, HlyF-associated OMVs were more prone to activate the non-canonical inflammasome pathway. Because autophagy and inflammation are crucial in the host's response to infection especially during sepsis, our findings revealed an unsuspected role of OMVs in the crosstalk between bacteria and their host, highlighting the fact that these extracellular vesicles have exacerbated pathogenic properties.
    Keywords:  Escherichia coli; HlyF; autophagy; inflammasome; outer membrane vesicle; pathogenesis
    DOI:  https://doi.org/10.1080/15548627.2022.2054040
  6. Apoptosis. 2022 Mar 21.
    Nobiletin as an inducer of programmed cell death in cancer: a review.
    Jun Huang, Zaoshang Chang, Quzhe Lu, Xuedong Chen, Masoud Najafi.
      Cancer resistance to therapy is a big issue in cancer therapy. Tumours may develop some mechanisms to reduce the induction of cell death, thus stimulating tumour growth. Cancer cells may show a low expression and activity of tumour suppressor genes and a low response to anti-tumour immunity. These mutations can increase the resistance of cancer cells to programmed cell death mechanisms such as apoptosis, ferroptosis, pyroptosis, autophagic cell death, and some others. The upregulation of some mediators and transcription factors such as Akt, nuclear factor of κB, signal transducer and activator of transcription 3, Bcl-2, and others can inhibit cell death in cancer cells. Using adjuvants to induce the killing of cancer cells is an interesting strategy in cancer therapy. Nobiletin (NOB) is a herbal-derived agent with fascinating anti-cancer properties. It has been shown to induce the generation of endogenous ROS by cancer cells, leading to damage to critical macromolecules and finally cell death. NOB may induce the activity of p53 and pro-apoptosis mediators, and also inhibit the expression and nuclear translocation of anti-apoptosis mediators. In addition, NOB may induce cancer cell killing by modulating other mechanisms that are involved in programmed cell death mechanisms. This review aims to discuss the cellular and molecular mechanisms of the programmed cell death in cancer by NOB via modulating different types of cell death in cancer.
    Keywords:  Apoptosis; Autophagy; Cancer; Cell death; NOB; Pyroptosis
    DOI:  https://doi.org/10.1007/s10495-022-01721-4
  7. Biochim Biophys Acta Rev Cancer. 2022 Mar 18. pii: S0304-419X(22)00049-X. [Epub ahead of print]1877(3): 188724
    Oncogenic viral infection and amino acid metabolism in cancer progression: Molecular insights and clinical implications.
    Na Liu, Feng Shi, Lifang Yang, Weihua Liao, Ya Cao.
      Viruses lack essential living system, so they must hijack host cell metabolism for its survival and reproduction. Interestingly, the metabolic reprogramming induced by oncovirus is critical for the malignant transformation. Amino acid can supply the source of nitrogen and carbon for biosynthesis or fulfill the energy requirement for the rapid growth of tumor cells. Amino acid metabolism caused by oncogenic viral infection often mirrors metabolic changes observed in cancer cells, such as glutamine addiction, asparagine dependence, arginine auxotrophy and active serine/ proline metabolism. In this review, we describe amino acid metabolism reprogramming in tumors. We also discuss how oncogenic viruses hijack amino acid metabolism in the stress status. Further research on the metabolic profile of virus-related cancers will not only provide new targets for tumor prevention and treatment, but novel diagnostic and therapeutic strategies as well.
    Keywords:  Amino acid metabolism; Infection-related carcinogenesis; Metabolic reprogramming; Oncogenic virus
    DOI:  https://doi.org/10.1016/j.bbcan.2022.188724
  8. Sci Rep. 2022 Mar 23. 12(1): 5052
    Activation of lysosomal mediated cell death in the course of autophagy by mTORC1 inhibitor.
    Sameer Ullah Khan, Anup Singh Pathania, Abubakar Wani, Kaneez Fatima, Mubashir Javed Mintoo, Baseerat Hamza, Masroor Ahmad Paddar, Wadhwa Bhumika, Loveleena Kour Anand, Mir Shahid Maqbool, Sameer Ahmad Mir, Jaspreet Kour, Vunnam Venkateswarlu, Dilip Manikrao Mondhe, Sanghapal D Sawant, Fayaz Malik.
      Lysosomal biogenesis plays a vital role in cell fate. Under certain conditions, excessive lysosomal biogenesis leads to susceptibility for lysosomal membrane permeabilization resulting in various pathological conditions including cell death. In cancer cells apoptosis machinery becomes dysregulated during the course of treatment, thus allows cancer cells to escape apoptosis. So it is therefore imperative to identify cytotoxic agents that exploit non-apoptotic mechanisms of cell death. Our study showed that pancreatic cancer cells treated with SDS-203 triggered an incomplete autophagic response and a nuclear translocation of transcriptional factor TFEB. This resulted in abundant biosynthesis and accumulation of autophagosomes and lysosomes into the cells leading to their death. It was observed that the silencing of autophagy genes didn't alter the cell fate, whereas siRNA-mediated silencing of TFEB subdued SDS-203 mediated lysosomal biogenesis and associated cell death. Further mouse tumors treated with SDS-203 showed a significant reduction in tumor burden and increased expression of lysosomal markers. Taken together this study demonstrates that SDS-203 treatment triggers non-apoptotic cell death in pancreatic cancer cells through a mechanism of lysosome over accumulation.
    DOI:  https://doi.org/10.1038/s41598-022-07955-1
  9. Nat Commun. 2022 Mar 22. 13(1): 1548
    S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions.
    Qiwei Jiang, Xiaomei Zhang, Xiaoming Dai, Shiyao Han, Xueji Wu, Lei Wang, Wenyi Wei, Ning Zhang, Wei Xie, Jianping Guo.
      Functioning as a master kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1) plays a fundamental role in phosphorylating and activating protein kinases A, B and C (AGC) family kinases, including AKT. However, upstream regulation of PDK1 remains largely elusive. Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT. Mechanistically, S6K1-mediated phosphorylation of PDK1 augments its interaction with 14-3-3 adaptor protein and homo-dimerization, subsequently dissociating PDK1 from phosphatidylinositol 3,4,5 triphosphate (PIP3) and retarding its interaction with AKT. Pathologically, tumor patient-associated PDK1 mutations, either attenuating S6K1-mediated PDK1 phosphorylation or impairing PDK1 interaction with 14-3-3, result in elevated AKT kinase activity and oncogenic functions. Taken together, our findings not only unravel a delicate feedback regulation of AKT signaling via S6K1-mediated PDK1 phosphorylation, but also highlight the potential strategy to combat mutant PDK1-driven cancers.
    DOI:  https://doi.org/10.1038/s41467-022-28910-8
  10. Cell Death Differ. 2022 Mar 24.
    Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer.
    Xiaopeng Xiong, Sumati Hasani, Lyndsay E A Young, Dylan R Rivas, Ashley T Skaggs, Rebecca Martinez, Chi Wang, Heidi L Weiss, Matthew S Gentry, Ramon C Sun, Tianyan Gao.
      Cancer cells are known for their ability to adapt variable metabolic programs depending on the availability of specific nutrients. Our previous studies have shown that uptake of fatty acids alters cellular metabolic pathways in colon cancer cells to favor fatty acid oxidation. Here, we show that fatty acids activate Drp1 to promote metabolic plasticity in cancer cells. Uptake of fatty acids (FAs) induces mitochondrial fragmentation by promoting ERK-dependent phosphorylation of Drp1 at the S616 site. This increased phosphorylation of Drp1 enhances its dimerization and interaction with Mitochondrial Fission Factor (MFF) at the mitochondria. Consequently, knockdown of Drp1 or MFF attenuates fatty acid-induced mitochondrial fission. In addition, uptake of fatty acids triggers mitophagy via a Drp1- and p62-dependent mechanism to protect mitochondrial integrity. Moreover, results from metabolic profiling analysis reveal that silencing Drp1 disrupts cellular metabolism and blocks fatty acid-induced metabolic reprograming by inhibiting fatty acid utilization. Functionally, knockdown of Drp1 decreases Wnt/β-catenin signaling by preventing fatty acid oxidation-dependent acetylation of β-catenin. As a result, Drp1 depletion inhibits the formation of tumor organoids in vitro and xenograft tumor growth in vivo. Taken together, our study identifies Drp1 as a key mediator that connects mitochondrial dynamics with fatty acid metabolism and cancer cell signaling.
    DOI:  https://doi.org/10.1038/s41418-022-00974-5
  11. Nat Commun. 2022 Mar 25. 13(1): 1627
    PUMILIO proteins promote colorectal cancer growth via suppressing p21.
    Yuanyuan Gong, Zukai Liu, Yihang Yuan, Zhenzhen Yang, Jiawei Zhang, Qin Lu, Wei Wang, Chao Fang, Haifan Lin, Sanhong Liu.
      PUMILIO (PUM) proteins belong to the highly conserved PUF family post-transcriptional regulators involved in diverse biological processes. However, their function in carcinogenesis remains under-explored. Here, we report that Pum1 and Pum2 display increased expression in human colorectal cancer (CRC). Intestine-specific knockout of Pum1 and Pum2 in mice significantly inhibits the progression of colitis-associated cancer in the AOM/DSS model. Knockout or knockdown of Pum1 and/or Pum2 in human CRC cells result in a significant decrease in the tumorigenicity and delayed G1/S transition. We identify p21/Cdkn1a as a direct target of PUM1. Abrogation of the PUM1 binding site in the p21 mRNA also results in decreased cancer cell growth and delayed G1/S transition. Furthermore, intravenous injection of nanoparticle-encapsulated anti-Pum1 and Pum2 siRNAs reduces colorectal tumor growth in murine orthotopic colon cancer models. These findings reveal the requirement of PUM proteins for CRC progression and their potential as therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-022-29309-1
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