bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2023‒03‒19
five papers selected by
Su Hyun Lee
Harvard University

  1. Nat Commun. 2023 Mar 13. 14(1): 1362
      Adipocytes robustly synthesize fatty acids (FA) from carbohydrate through the de novo lipogenesis (DNL) pathway, yet surprisingly DNL contributes little to their abundant triglyceride stored in lipid droplets. This conundrum raises the hypothesis that adipocyte DNL instead enables membrane expansions to occur in processes like autophagy, which requires an abundant supply of phospholipids. We report here that adipocyte Fasn deficiency in vitro and in vivo markedly impairs autophagy, evident by autophagosome accumulation and severely compromised degradation of the autophagic substrate p62. Our data indicate the impairment occurs at the level of autophagosome-lysosome fusion, and indeed, loss of Fasn decreases certain membrane phosphoinositides necessary for autophagosome and lysosome maturation and fusion. Autophagy dependence on FA produced by Fasn is not fully alleviated by exogenous FA in cultured adipocytes, and interestingly, imaging studies reveal that Fasn colocalizes with nascent autophagosomes. Together, our studies identify DNL as a critical source of FAs to fuel autophagosome and lysosome maturation and fusion in adipocytes.
  2. Mol Cancer Res. 2023 Mar 17. pii: MCR-22-0825. [Epub ahead of print]
      Recent studies have shown that autophagy plays an important role in gynecological tumours, and ubiquitin modification of autophagy regulatory components is essential to regulate autophagic. In this study, we found that UBE2C affects endometrial cancer cell apoptosis and proliferation by inhibiting autophagy. Electron microscopy observation of cell ultrastructure and experimental biochemical analysis showed that EC cells with UBE2C expression knocked down display typical autophagic characteristics. Cells were cotreated with the autophagy pharmacological inhibitors chloroquine and/or bafilomycin A1, and mRFP-GFP-LC3 assays were performed to monitor autophagic flux and determine whether UBE2C suppresses the autophagy program. Investigation of the corresponding mechanism by which UBE2C inhibits autophagy revealed that UBE2C induces K48-linked SIRT1 ubiquitination and promotes ubiquitination-dependent degradation of SIRT1, subsequently reducing H4K16 deacetylation levels and epigenetically inhibiting the expression of autophagy-related genes. The results of CCK-8, Hoechst staining, and immunofluorescence assays further indicated that deletion of the autophagy-related gene BECN1 significantly attenuates UBE2C knockdown-induced cell apoptosis. Moreover, overexpression of UBE2C promoted tumor growth in the xenograft mice model. While, the introduction of rapamycin, an agonist of autophagy, successfully reversed tumor growth and apoptosis inhibition mediated by UBE2C overexpression in vitro and in vivo. Taken together, our results suggested that UBE2C-mediated ubiquitination and degradation of SIRT1 contribute to the malignant progression of endometrial cancer through epigenetic inhibition of autophagy. Implications: Our study highlights the tumorigenic role and regulatory mechanism of UBE2C in EC; UBE2C inhibits EC cell apoptosis through autophagy-related mechanisms and our findings provide new insights into the treatment of endometrial cancer.
  3. Mol Med. 2023 Mar 14. 29(1): 34
      The homologous to the E6-AP carboxyl terminus (HECT)-type E3 ubiquitin ligases are the selective executers in the protein ubiquitination, playing a vital role in modulation of the protein function and stability. Evidence shows the regulatory role of HECT-type E3 ligases in various steps of the autophagic process. Autophagy is an intracellular digestive and recycling process that controls the cellular hemostasis. Defective autophagy is involved in tumorigenesis and has been detected in various types of cancer cells. A growing body of findings indicates that HECT-type E3 ligases, in particular members of the neural precursor cell expressed developmentally downregulated protein 4 (NEDD4) including NEDD4-1, NEDD4-L, SMURFs, WWPs, and ITCH, play critical roles in dysregulation or dysfunction of autophagy in cancer cells. The present review focuses on NEDD4 E3 ligases involved in defective autophagy in cancer cells and discusses their autophagic function in different cancer cells as well as substrates and the signaling pathways in which they participate, conferring a basis for the cancer treatment through the modulating of these E3 ligases.
    Keywords:  Autophagy; Cancer; E3 ligase; NEDD4; Ubiquitin
  4. Autophagy. 2023 Mar 16.
      The critical intracellular pattern recognition receptor NLRP3 senses pathogenic organisms and endogenous danger signals via forming inflammasomes to orchestrate innate immune responses. Dysfunction of NLRP3 inflammasomes is implicated in several inflammatory disorders. Hence, it is important to uncover the mechanisms preventing sustained NLRP3 inflammasome activation. Recently, we revealed that ZDHHC12-mediated palmitoylation enhances NLRP3 degradation through the chaperone-mediated autophagy pathway, and identified gain-of-function variants of NLRP3 in autoinflammatory disease, which induce excessive NLRP3 inflammasome activation through decreased palmitoylation level and impaired chaperone-mediated autophagic degradation.
    Keywords:  NLRP3; chaperone-mediated autophagy; inflammasome; inflammation; palmitoylation
  5. Cell Death Dis. 2023 Mar 11. 14(3): 191
      Pancreatic cancer remains one of the most lethal diseases with a relatively low 5-year survival rate, and gemcitabine-based chemoresistance occurs constantly. Mitochondria, as the power factory in cancer cells, are involved in the process of chemoresistance. The dynamic balance of mitochondria is under the control of mitophagy. Stomatin-like protein 2 (STOML2) is located in the mitochondrial inner membrane and is highly expressed in cancer cells. In this study, using a tissue microarray (TMA), we found that high STOML2 expression was correlated with higher survival of patients with pancreatic cancer. Meanwhile, the proliferation and chemoresistance of pancreatic cancer cells could be retarded by STOML2. In addition, we found that STOML2 was positively related to mitochondrial mass and negatively related to mitophagy in pancreatic cancer cells. STOML2 stabilized PARL and further prevented gemcitabine-induced PINK1-dependent mitophagy. We also generated subcutaneous xenografts to verify the enhancement of gemcitabine therapy induced by STOML2. These findings suggested that STOML2 regulated the mitophagy process through the PARL/PINK1 pathway, thereby reducing the chemoresistance of pancreatic cancer. STOML2-overexpression targeted therapy might be helpful for gemcitabine sensitization in the future.