bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2022–10–09
six papers selected by
Su Hyun Lee, Seoul National University
  1. Autophagy induction promoted by m6A reader YTHDF3 through translation upregulation of FOXO3 mRNA.
  2. Role of K63-linked ubiquitination in cancer.
  3. RHOA, a small G-protein, signals to mitophagy through regulation of PINK1 protein stability and protects cardiomyocytes against ischemia.
  4. A Noncanonical Autophagy Function of ATG9A for Golgi Integrity and Dynamics.
  5. Regulation of KDM5C stability and enhancer reprogramming in breast cancer.
  6. Mitophagy: A novel perspective for insighting into cancer and cancer treatment.
  1. Nat Commun. 2022 Oct 04. 13(1): 5845
    Autophagy induction promoted by m6A reader YTHDF3 through translation upregulation of FOXO3 mRNA.
    WeiChao Hao, MeiJuan Dian, Ying Zhou, QiuLing Zhong, WenQian Pang, ZiJian Li, YaYan Zhao, JiaCheng Ma, XiaoLin Lin, RenRu Luo, YongLong Li, JunShuang Jia, HongFen Shen, ShiHao Huang, GuanQi Dai, JiaHong Wang, Yan Sun, Dong Xiao.
      Autophagy is crucial for maintaining cellular energy homeostasis and for cells to adapt to nutrient deficiency, and nutrient sensors regulating autophagy have been reported previously. However, the role of eiptranscriptomic modifications such as m6A in the regulation of starvation-induced autophagy is unclear. Here, we show that the m6A reader YTHDF3 is essential for autophagy induction. m6A modification is up-regulated to promote autophagosome formation and lysosomal degradation upon nutrient deficiency. METTL3 depletion leads to a loss of functional m6A modification and inhibits YTHDF3-mediated autophagy flux. YTHDF3 promotes autophagy by recognizing m6A modification sites around the stop codon of FOXO3 mRNA. YTHDF3 also recruits eIF3a and eIF4B to facilitate FOXO3 translation, subsequently initiating autophagy. Overall, our study demonstrates that the epitranscriptome regulator YTHDF3 functions as a nutrient responder, providing a glimpse into the post-transcriptional RNA modifications that regulate metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s41467-022-32963-0
  2. Cell Death Discov. 2022 Oct 06. 8(1): 410
    Role of K63-linked ubiquitination in cancer.
    Liangzi Cao, Xiaofang Liu, Bowen Zheng, Chengzhong Xing, Jingwei Liu.
      Ubiquitination is a critical type of post-translational modifications, of which K63-linked ubiquitination regulates interaction, translocation, and activation of proteins. In recent years, emerging evidence suggest involvement of K63-linked ubiquitination in multiple signaling pathways and various human diseases including cancer. Increasing number of studies indicated that K63-linked ubiquitination controls initiation, development, invasion, metastasis, and therapy of diverse cancers. Here, we summarized molecular mechanisms of K63-linked ubiquitination dictating different biological activities of tumor and highlighted novel opportunities for future therapy targeting certain regulation of K63-linked ubiquitination in tumor.
    DOI:  https://doi.org/10.1038/s41420-022-01204-0
  3. Autophagy. 2022 Oct 06.
    RHOA, a small G-protein, signals to mitophagy through regulation of PINK1 protein stability and protects cardiomyocytes against ischemia.
    Michelle Tu, Shigeki Miyamoto.
      RHOA (ras homolog family member A) is a small G-protein that regulates a range of cellular processes including cell growth and survival. RHOA is a proximal downstream effector of G protein-coupled receptor coupling to GNA12/Gα12-GNA13/Gα13 proteins, and is activated in response to stretch and oxidative stress, functioning as a stress-response molecule. It has been demonstrated that RHOA signaling provides cardioprotection through inhibition of mitochondrial death pathways. Mitochondrial integrity is preserved not only by inhibition of mitochondrial death pathways but also by mitochondrial quality control mechanisms including mitophagy. One of the most well-established mechanisms of mitophagy is the mitochondrial membrane depolarization-dependent PINK1-PRKN/Parkin pathway. However, depolarization of the mitochondrial membrane potential is a late-stage event that occurs just before cell death, and additional intracellular mechanisms that enhance the PINK1-PRKN pathway have not been fully determined. We recently discovered that RHOA activation engages a unique mechanism to regulate PINK1 protein stability without inducing mitochondrial membrane depolarization, leading to increased mitophagy and protection against ischemia in cardiomyocytes. Our results suggest regulation of RHOA signaling as a potential strategy to enhance protective mitophagy against stress without compromising mitochondrial functions.
    Keywords:  Cardiomyocytes; PINK1, RHOA; ischemia; mitophagy, Parkin
    DOI:  https://doi.org/10.1080/15548627.2022.2132707
  4. Autophagy. 2022 Oct 05.
    A Noncanonical Autophagy Function of ATG9A for Golgi Integrity and Dynamics.
    Yuanyuan Meng, Qian Luo, Quan Chen, Yushan Zhu.
      In mammalian cells, the Golgi apparatus serves as the central hub for membrane trafficking. Notably, the membrane trafficking and Golgi integrity are tightly regulated by reversible post-translational modifications, such as glycosylation, phosphorylation and ubiquitination. Nonetheless, how the Golgi apparatus responses to stress to ensure appropriate membrane assembly and distribution of cargo is poorly understood. The Golgi resident protein ATG9A is the only multi-spanning membrane protein in the ATG family, and has been demonstrated to traffic through the plasma membrane, endosomes, and Golgi to deliver materials for the initiation of macroautophagy/autophagy. Our recent work reveals a noncanonical function of ATG9A for Golgi dynamics and identifies a pathway for sensing Golgi stress via the MARCHF9-ATG9A axis.
    Keywords:  ATG9A; Golgi dynamics; Golgi stress response; MARCHF9; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2022.2131244
  5. Cell Death Dis. 2022 Oct 03. 13(10): 843
    Regulation of KDM5C stability and enhancer reprogramming in breast cancer.
    Qiong Xiao, Chen-Yu Wang, Chuan Gao, Ji-Dong Chen, Jing-Jing Chen, Zhen Wang, Lin-Gao Ju, Shan-Bo Tang, Jie Yao, Feng Li, Lian-Yun Li, Min Wu.
      Abnormality of enhancer regulation has emerged as one of the critical features for cancer cells. KDM5C is a histone H3K4 demethylase and frequently mutated in several types of cancer. It is critical for H3K4me3 and activity of enhancers, but its regulatory mechanisms remain elusive. Here, we identify TRIM11 as one ubiquitin E3 ligase for KDM5C. TRIM11 interacts with KDM5C, catalyzes K48-linked ubiquitin chain on KDM5C, and promotes KDM5C degradation through proteasome. TRIM11 deficiency in an animal model represses the growth of breast tumor and stabilizes KDM5C. In breast cancer patient tissues, TRIM11 is highly expressed and KDM5C is lower expressed, and their expression is negatively correlated. Mechanistically, TRIM11 regulates the enhancer activity of genes involved in cell migration and immune response by targeting KDM5C. TRIM11 and KDM5C regulate MCAM expression and cell migration through targeting H3K4me3 on MCAM enhancer. Taken together, our study reveals novel mechanisms for enhancer regulation during breast cancer tumorigenesis and development.
    DOI:  https://doi.org/10.1038/s41419-022-05296-5
  6. Cell Prolif. 2022 Oct 05. e13327
    Mitophagy: A novel perspective for insighting into cancer and cancer treatment.
    Congkuan Song, Shize Pan, Jinjin Zhang, Ning Li, Qing Geng.
       BACKGROUND: Mitophagy refers to the selective self-elimination of mitochondria under damaged or certain developmental conditions. As an important regulatory mechanism to remove damaged mitochondria and maintain the internal and external cellular balance, mitophagy plays pivotal roles in carcinogenesis and progression as well as treatment.
    MATERIALS AND METHODS: Here, we combined data from recent years to comprehensively describe the regulatory mechanisms of mitophagy and its multifaceted significance in cancer, and discusse the potential of targeted mitophagy as a cancer treatment strategy.
    RESULTS: The molecular mechanisms regulating mitophagy are complex, diverse, and cross-talk. Inducing or blocking mitophagy has the same or completely different effects in different cancer contexts. Mitophagy plays an indispensable role in regulating cancer metabolic reprogramming, cell stemness, and chemotherapy resistance for better adaptation to tumor microenvironment. In cancer cell biology, mitophagy is considered to be a double-edged sword. And to fully understand the role of mitophagy in cancer development can provide new targets for cancer treatment in clinical practice.
    CONCLUSIONS: This review synthesizes a large body of data to comprehensively describe the molecular mechanisms of mitophagy and its multidimensional significance in cancer and cancer treatment, which will undoubtedly deepen the understanding of mitophagy.
    DOI:  https://doi.org/10.1111/cpr.13327
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