bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2021‒05‒30
ten papers selected by
Su Hyun Lee
Seoul National University
  1. AMPKα loss promotes KRAS-mediated lung tumorigenesis.
  2. Tumor-derived exosomal components: the multifaceted roles and mechanisms in breast cancer metastasis.
  3. Acetylation-dependent regulation of TPD52 isoform 1 modulates chaperone-mediated autophagy in prostate cancer.
  4. KLHL38 involvement in non-small cell lung cancer progression via activation of the Akt signaling pathway.
  5. Caspase-8: A key protein of cross-talk signal way in "PANoptosis" in cancer.
  6. Small but mighty: Atg8s and Rabs in Membrane Dynamics during Autophagy.
  7. Autophagy in metabolism and quality control: opposing, complementary or interlinked functions?
  8. Emerging roles of ATG proteins and membrane lipids in autophagosome formation.
  9. Regulation of autophagy by VPS34 branched ubiquitination controls proteostasis and liver metabolism.
  10. Molecular recognition and deubiquitination of cyclic K48-linked ubiquitin chains by OTUB1.
  1. Cell Death Differ. 2021 May 26.
    AMPKα loss promotes KRAS-mediated lung tumorigenesis.
    Manuela La Montagna, Lei Shi, Peter Magee, Sudhakar Sahoo, Matteo Fassan, Michela Garofalo.
      AMP-activated protein kinase (AMPK) is a critical sensor of energy status that coordinates cell growth with energy balance. In non-small cell lung cancer (NSCLC) the role of AMPKα is controversial and its contribution to lung carcinogenesis is not well-defined. Furthermore, it remains largely unknown whether long non-coding RNAs (lncRNAs) are involved in the regulation of AMPK-mediated pathways. Here, we found that loss of AMPKα in combination with activation of mutant KRASG12D increased lung tumour burden and reduced survival in KrasLSLG12D/+/AMPKαfl/fl mice. In agreement, functional in vitro studies revealed that AMPKα silencing increased growth and migration of NSCLC cells. In addition, we identified an AMPKα-modulated lncRNA, KIMAT1 (ENSG00000228709), which in turn regulates AMPKα activation by stabilizing the lactate dehydrogenase B (LDHB). Collectively, our study indicates that AMPKα loss promotes KRAS-mediated lung tumorigenesis and proposes a novel KRAS/KIMAT1/LDHB/AMPKα axis that could be exploited for therapeutic purposes.
    DOI:  https://doi.org/10.1038/s41418-021-00777-0
  2. Cell Death Dis. 2021 May 26. 12(6): 547
    Tumor-derived exosomal components: the multifaceted roles and mechanisms in breast cancer metastasis.
    Yufang Tan, Xiao Luo, Wenchang Lv, Weijie Hu, Chongru Zhao, Mingchen Xiong, Yi Yi, Dawei Wang, Yichen Wang, Haiping Wang, Yiping Wu, Qi Zhang.
      Breast cancer (BC) is the most frequently invasive malignancy and the leading cause of tumor-related mortality among women worldwide. Cancer metastasis is a complex, multistage process, which eventually causes tumor cells to colonize and grow at the metastatic site. Distant organ metastases are the major obstacles to the management of advanced BC patients. Notably, exosomes are defined as specialized membrane-enclosed extracellular vesicles with specific biomarkers, which are found in a wide variety of body fluids. Recent studies have demonstrated that exosomes are essential mediators in shaping the tumor microenvironment and BC metastasis. The transferred tumor-derived exosomes modify the capability of invasive behavior and organ-specific metastasis in recipient cells. BC exosomal components, mainly including noncoding RNAs (ncRNAs), proteins, lipids, are the most investigated components in BC metastasis. In this review, we have emphasized the multifaceted roles and mechanisms of tumor-derived exosomes in BC metastasis based on these important components. The underlying mechanisms mainly include the invasion behavior change, tumor vascularization, the disruption of the vascular barrier, and the colonization of the targeted organ. Understanding the significance of tumor-derived exosomal components in BC metastasis is critical for yielding novel routes of BC intervention.
    DOI:  https://doi.org/10.1038/s41419-021-03825-2
  3. Autophagy. 2021 May 26. 1-15
    Acetylation-dependent regulation of TPD52 isoform 1 modulates chaperone-mediated autophagy in prostate cancer.
    Yizeng Fan, Tao Hou, Yang Gao, Weichao Dan, Tianjie Liu, Bo Liu, Yule Chen, Hongjun Xie, Zhao Yang, Jiaqi Chen, Jin Zeng, Lei Li.
      Aberrant chaperone-mediated autophagy (CMA) activation has been suggested as a tumorigenesis-promoting event in various cancers, although its roles in prostate cancer (PCa) remain elusive. Emerging evidence indicates that TPD52 isoform 1, a prostate-specific and androgen-responsive gene, contributes to the malignant progression of PCa. Here, we demonstrate that TPD52 enhances CMA activation by interacting with HSPA8/HSC70 and enhancing substrate degradation in PCa. Elevation of TPD52 is essential for CMA-induced PCa cell proliferation and stress resistance in vitro and in vivo. Furthermore, TPD52 is acetylated by KAT2B at K163, which is a process that can be antagonized by HDAC2. Inactivation of HDAC2 results in elevated TPD52 acetylation, which compromises the interaction between TPD52 and HSPA8, leading to impaired CMA function and tumor growth in vivo. Taken together, our findings reveal that acetylation-dependent regulation of TPD52 modulates CMA oncogenic function in PCa, thereby suggesting the possibility of targeting the TPD52-mediated CMA pathway to control the progression of PCa.Abbreviations: CMA: chaperone-mediated autophagy; HDAC2: histone deacetylase 2; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KAT2B: lysine acetyltransferase 2B; LAMP2A: lysosomal associated membrane protein 2A; PCa: prostate cancer; TPD52: tumor protein D52.
    Keywords:  Chaperone-mediated autophagy; HDAC2; HSPA8; KAT2B; TPD52 isoform 1; prostate cancer
    DOI:  https://doi.org/10.1080/15548627.2021.1917130
  4. Cell Death Dis. 2021 May 28. 12(6): 556
    KLHL38 involvement in non-small cell lung cancer progression via activation of the Akt signaling pathway.
    Yitong Xu, Chenglong Wang, Xizi Jiang, Yao Zhang, Hongbo Su, Jun Jiang, Hongjiu Ren, Xueshan Qiu.
      Lung cancer is the leading cause of cancer-related death worldwide. KLHL38 has been reported to be upregulated during diapause but downregulated after androgen treatment during the reversal of androgen-dependent skeletal muscle atrophy. This study aimed to clarify the role of KLHL38 in non-small cell lung cancer (NSCLC). KLHL38 expression was evaluated in tumor and adjacent normal tissues from 241 patients with NSCLC using immunohistochemistry and real-time PCR, and its association with clinicopathological parameters was analyzed. KLHL38 levels positively correlated with tumor size, lymph node metastasis, and pathological tumor-node-metastasis stage (all P < 0.001). In NSCLC cell lines, KLHL38 overexpression promoted PTEN ubiquitination, thereby activating Akt signaling. It also promoted cell proliferation, migration, and invasion by upregulating the expression of genes encoding cyclin D1, cyclin B, c-myc, RhoA, and MMP9, while downregulating the expression of p21 and E-cadherin. In vivo experiments in nude mice further confirmed that KLHL38 promotes NSCLC progression through Akt signaling pathway activation. Together, these results indicate that KLHL38 is a valuable candidate prognostic biomarker and potential therapeutic target for NSCLC.
    DOI:  https://doi.org/10.1038/s41419-021-03835-0
  5. Int J Cancer. 2021 May 24.
    Caspase-8: A key protein of cross-talk signal way in "PANoptosis" in cancer.
    Mingxia Jiang, Ling Qi, Lisha Li, Yiming Wu, Dongfeng Song, Yanjing Li.
      Cysteinyl aspartate specific proteinase (Caspase)-8 has long been considered a promoter of apoptosis and part of the mechanism by which cytotoxic drugs kill cancer cells. With the continuous exploration of the types of programmed cell death, an increasing number of studies have confirmed that caspase-8 plays an important role in cancer. Recently, scholars have proposed the term "PANoptosis", which mainly includes three programmed cell death modes, namely pyroptosis, apoptosis, and necroptosis. In addition to mediating endogenous apoptotic pathways, caspase-8 can also participate in the cleavage of gasdermin (GSDM) family proteins to induce pyroptosis. Furthermore, the expression of enzymatically inactive caspase-8 (C362S) can cause embryonic lethality and inflammatory tissue destruction in mice by inducing necroptosis and pyroptosis. Therefore, the activation and deletion of caspase-8 enzyme activity, as well as the knockout of the coding gene, are closely related to "PANoptosis". In addition, caspase-8 can also improve the tumor microenvironment and enhance tumor anti-immunity. Studies have shown that caspase-8 is also associated with tumor growth and invasion, angiogenesis and metastasis, therapeutic resistance, and poor clinical outcomes. Therefore, it is very important to measure the cancer-promoting and anti-cancer effects of caspase-8 and find a balance, and to study its role in the effect of "PANoptosis" in depth. This article reviews the role of caspase-8 in "PANoptosis" in cancer to provide new strategies and targets for cancer. This article is protected by copyright. All rights reserved.
    Keywords:  Caspase-8; apoptosis; cancer; necroptosis; pyroptosis
    DOI:  https://doi.org/10.1002/ijc.33698
  6. Biochim Biophys Acta Mol Cell Res. 2021 May 25. pii: S0167-4889(21)00118-X. [Epub ahead of print] 119064
    Small but mighty: Atg8s and Rabs in Membrane Dynamics during Autophagy.
    Saskia Barz, Franziska Kriegenburg, Pablo Sánchez-Martín, Claudine Kraft.
      Autophagy is a degradative pathway during which autophagosomes are formed that enwrap cytosolic material destined for turnover within the lytic compartment. Autophagosome biogenesis requires controlled lipid and membrane rearrangements to allow the formation of an autophagosomal seed and its subsequent elongation into a fully closed and fusion-competent double membrane vesicle. Different membrane remodeling events are required, which are orchestrated by the distinct autophagy machinery. An important player among these autophagy proteins is the small lipid-modifier Atg8. Atg8 proteins facilitate various aspects of autophagosome formation and serve as a binding platform for autophagy factors. Also Rab GTPases have been implicated in autophagosome biogenesis. As Atg8 proteins interact with several Rab GTPase regulators, they provide a possible link between autophagy progression and Rab GTPase activity. Here, we review central aspects in membrane dynamics during autophagosome biogenesis with a focus on Atg8 proteins and selected Rab GTPases.
    Keywords:  Atg8 proteins; Rab GTPases; autophagy; membrane dynamics
    DOI:  https://doi.org/10.1016/j.bbamcr.2021.119064
  7. Autophagy. 2021 May 26.
    Autophagy in metabolism and quality control: opposing, complementary or interlinked functions?
    Vojo Deretic, Guido Kroemer.
      The sensu stricto autophagy, macroautophagy, is considered to be both a metabolic process as well as a bona fide quality control process. The question as to how these two aspects of autophagy are coordinated and whether and why they overlap has implications for fundamental aspects, pathophysiological effects, and pharmacological manipulation of autophagy. At the top of the regulatory cascade controlling autophagy are master regulators of cellular metabolism, such as MTOR and AMPK, which render the system responsive to amino acid and glucose starvation. At the other end exists a variety of specific autophagy receptors, engaged in the selective removal of a diverse array of intracellular targets, from protein aggregates/condensates to whole organelles such as mitochondria, ER, peroxisomes, lysosomes and lipid droplets. Are the roles of autophagy in metabolism and quality control mutually exclusive, independent or interlocked? How are priorities established? What are the molecular links between both phenomena? This article will provide a starting point to formulate these questions, the responses to which should be taken into consideration in future autophagy-based interventions.
    Keywords:  AMPK; ATG; Aging; Akt; Alzheimer’s disease; ESCRT; FOXO; LC3; MTOR; NAD; NASH; Obesity; Parkinson’s Disease; RagA/B; SIRT1; SIRT3; Selective autophagy; TBK1; TCA; TFEB; Tor; acetyl CoA; autophagy; calcienurin; cancer; cardiovascular; diabetes; endoplasmic reticulum; fatty acids; ferritin; galectin; glycogen; glycolysis; heart; immunity; infection; insulin; lipid droplets; liver; lysosomes; metabolism; mitochondria; mitophagy; neurodegeneration; nutrition; oxidative phosphorylation; p62 SQSTM1; peroxisome; quality control; sirtuin
    DOI:  https://doi.org/10.1080/15548627.2021.1933742
  8. Cell Discov. 2020 May 26. 6(1): 32
    Emerging roles of ATG proteins and membrane lipids in autophagosome formation.
    Taki Nishimura, Sharon A Tooze.
      Autophagosome biogenesis is a dynamic membrane event, which is executed by the sequential function of autophagy-related (ATG) proteins. Upon autophagy induction, a cup-shaped membrane structure appears in the cytoplasm, then elongates sequestering cytoplasmic materials, and finally forms a closed double membrane autophagosome. However, how this complex vesicle formation event is strictly controlled and achieved is still enigmatic. Recently, there is accumulating evidence showing that some ATG proteins have the ability to directly interact with membranes, transfer lipids between membranes and regulate lipid metabolism. A novel role for various membrane lipids in autophagosome formation is also emerging. Here, we highlight past and recent key findings on the function of ATG proteins related to autophagosome biogenesis and consider how ATG proteins control this dynamic membrane formation event to organize the autophagosome by collaborating with membrane lipids.
    DOI:  https://doi.org/10.1038/s41421-020-0161-3
  9. Mol Cell Oncol. 2021 ;8(3): 1915076
    Regulation of autophagy by VPS34 branched ubiquitination controls proteostasis and liver metabolism.
    Yu-Hsuan Chen, Ruey-Hwa Chen.
      Ubiquitin-proteasome system and autophagy are the two major recycling processes. Our recent work uncovers a K29/K48 branched ubiquitination on the phosphatidylinositol 3-kinase catalytic subunit type 3 (PI3KC3, best known as VPS34). This ubiquitination is positively or negatively regulated under pathophysiological conditions to influence on autophagy, proteostasis and lipid homeostasis.
    Keywords:  Autophagy; branched ubiquitination; liver steatosis; protein quality control; vps34
    DOI:  https://doi.org/10.1080/23723556.2021.1915076
  10. Biochem Biophys Res Commun. 2021 May 25. pii: S0006-291X(21)00802-0. [Epub ahead of print]562 94-99
    Molecular recognition and deubiquitination of cyclic K48-linked ubiquitin chains by OTUB1.
    Tomoki Sorada, Daichi Morimoto, Erik Walinda, Kenji Sugase.
      Conjugation of K48-linked ubiquitin chains to intracellular proteins mainly functions as a signal for proteasomal degradation. The conjugating enzyme E2-25K synthesizes not only canonical (noncyclic) but also cyclic K48-linked ubiquitin chains. Although the cyclic conformation is expected to repress molecular recognition by ubiquitin binding proteins due to restricting the flexibility of the ubiquitin subunits in a chain, multiple proteins are reported to associate with cyclic ubiquitin chains similar to noncyclic chains. However, the molecular mechanism of how cyclic ubiquitin chains are recognized remains unclear. Here we investigated the effect of cyclization on ubiquitin-chain cleavage and molecular recognition by a K48-linkage specific deubiquitinating enzyme OTUB1 for cyclic diubiquitin by NMR spectroscopic analyses. Compared to noncyclic diubiquitin, we observed slow but unambiguously detectable cleavage of cyclic diubiquitin to monoubiquitin by OTUB1. Intriguingly, upon ubiquitin chain cleavage, cyclic diubiquitin appeared to alter its "autoinhibited" conformation to an incompletely but partially accessible conformation, induced by interaction with OTUB1 via the ubiquitin-subunit specific recognition patches and adjacent surfaces. These data imply that cyclic ubiquitin chains may exist stably in cells in spite of the presence of deubiquitinating enzymes and that these chains can be recognized by intracellular proteins in a manner distinct from that of noncyclic ubiquitin chains.
    Keywords:  Cyclic ubiquitin; Deubiquitination; K48-linked ubiquitin chains; NMR; OTUB1
    DOI:  https://doi.org/10.1016/j.bbrc.2021.05.031
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