bims-lymeca Biomed News
on Lysosome metabolism in cancer
Issue of 2022‒11‒13
seven papers selected by
Harilaos Filippakis
University of New England
  1. An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss.
  2. The interdependent transport of yeast vacuole Ca2+ and H+ and the role of Phosphatidylinositol 3,5-bisphosphate.
  3. How cells recognize and remove the perforated lysosome.
  4. Targeted delivery of liposomal chemoimmunotherapy for cancer treatment.
  5. Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR.
  6. Metabolism of Selenium, Selenocysteine, and Selenoproteins in Ferroptosis in Solid Tumor Cancers.
  7. Inhibited transcription factor EB function induces reactive oxygen species overproduction to promote pyroptosis in cadmium-exposed renal tubular epithelial cells.
  1. Nat Commun. 2022 Nov 10. 13(1): 6808
    An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss.
    Kaushal Asrani, Juhyung Woo, Adrianna A Mendes, Ethan Schaffer, Thiago Vidotto, Clarence Rachel Villanueva, Kewen Feng, Lia Oliveira, Sanjana Murali, Hans B Liu, Daniela C Salles, Brandon Lam, Pedram Argani, Tamara L Lotan.
      The mechanistic target of rapamycin complex 1 (mTORC1) integrates inputs from growth factors and nutrients, but how mTORC1 autoregulates its activity remains unclear. The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1 following lysosomal recruitment by RagC/D GTPases in response to amino acid stimulation. We find that starvation-induced lysosomal localization of the RagC/D GAP complex, FLCN:FNIP2, is markedly impaired in a mTORC1-sensitive manner in renal cells with TSC2 loss, resulting in unexpected TFEB hypophosphorylation and activation upon feeding. TFEB phosphorylation in TSC2-null renal cells is partially restored by destabilization of the lysosomal folliculin complex (LFC) induced by FLCN mutants and is fully rescued by forced lysosomal localization of the FLCN:FNIP2 dimer. Our data indicate that a negative feedback loop constrains amino acid-induced, FLCN:FNIP2-mediated RagC activity in renal cells with constitutive mTORC1 signaling, and the resulting MiT/TFE hyperactivation may drive oncogenesis with loss of the TSC2 tumor suppressor.
    DOI:  https://doi.org/10.1038/s41467-022-34617-7
  2. J Biol Chem. 2022 Nov 02. pii: S0021-9258(22)01115-2. [Epub ahead of print] 102672
    The interdependent transport of yeast vacuole Ca2+ and H+ and the role of Phosphatidylinositol 3,5-bisphosphate.
    Chi Zhang, Yilin Feng, Adam Balutowski, Gregory E Miner, David A Rivera-Kohr, Michael R Hrabak, Katherine D Sullivan, Annie Guo, Jorge D Calderin, Rutilio A Fratti.
      Yeast vacuoles are acidified by the v-type H+-ATPase (V-ATPase) that is comprised of the membrane embedded VO complex and the soluble cytoplasmic V1 complex. The assembly of the V1-VO holoenzyme on the vacuole is stabilized in part through interactions between the VO a-subunit ortholog Vph1 and the lipid phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2). PI(3,5)P2 also affects vacuolar Ca2+ release through the channel Yvc1, and uptake through the Ca2+ pump Pmc1. Here we asked if H+ and Ca2+ transport activities were connected through PI(3,5)P2. We found that overproduction of PI(3,5)P2 by the hyperactive fab1T2250A mutant augmented vacuole acidification, whereas the kinase-inactive fab1EEE mutant attenuated the formation of a H+ gradient. Separately, we tested the effects of excess Ca2+ on vacuole acidification. Adding micromolar Ca2+ blocked vacuole acidification, whereas chelating Ca2+ accelerated acidification. The effect of adding Ca2+ on acidification was eliminated when the Ca2+/H+ antiporter Vcx1 was absent, indicating that the vacuolar H+ gradient can collapse during Ca2+ stress through Vcx1 activity. This, however was independent of PI(3,5)P2, suggesting that PI(3,5)P2 plays a role in sub-micromolar Ca2+ flux, but not under Ca2+ shock. To see if the link between Ca2+ and H+ transport was bidirectional we examined Ca2+ transport when vacuole acidification was inhibited. We found that Ca2+ transport was inhibited by halting V-ATPase activity with Bafilomycin or neutralizing vacuolar pH with chloroquine. Together, these data show that Ca2+ transport and V-ATPase efficacy are connected but not necessarily through PI(3,5)P2.
    Keywords:  Calcium ATPase; Calcium Transport; Fab1; Lysosome; PIKfyve; Phosphoinositide; Pmc1; Stv1; V-ATPase; Vcx1; Vph1; organellar pH homeostasis
    DOI:  https://doi.org/10.1016/j.jbc.2022.102672
  3. Autophagy. 2022 Nov 11. 1-3
    How cells recognize and remove the perforated lysosome.
    Keisuke Tabata, Marika Saeki, Tamotsu Yoshimori, Maho Hamasaki.
      Macroautophagy (hereafter autophagy) is a highly conserved intracellular degradation system to maintain cellular homeostasis by degrading cellular components such as misfolded proteins, nonfunctional organelles, pathogens, and cytosol. Conversely, selective autophagy targets and degrades specific cargo, such as organelles, bacteria, etc. We previously reported that damaged lysosomes are autophagy targets, via a process called lysophagy. However, how cells target damaged lysosomes through autophagy is not known. We performed proteomics analysis followed by siRNA screening to identify genes involved in targeting damaged lysosomes and identified a new E3 ligase complex, involving CUL4A (cullin 4A), as a regulatory complex in lysophagy. We also found that this complex mediates K48-linked poly-ubiquitination on lysosome protein LAMP2 during lysosomal damage; particularly, the lumenal side of LAMP2 is important to recruit the complex to damaged lysosomes. This protein modification is thus critical to initiate the clearance of damaged lysosomes.
    Keywords:  CUL4A; LAMP2; lysophagy; lysosomal membrane damage; selective autophagy; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2022.2138686
  4. Front Immunol. 2022 ;13 1010021
    Targeted delivery of liposomal chemoimmunotherapy for cancer treatment.
    Yusheng Liu, Joonsu Han, Yang Bo, Rimsha Bhatta, Hua Wang.
      Chemoimmunotherapy that utilizes the immunomodulatory effect of chemotherapeutics has shown great promise for treating poorly immunogenic solid tumors. However, there remains a significant room for improving the synergy between chemotherapy and immunotherapy, including the efficient, concurrent delivery of chemotherapeutics and immunomodulators into tumors. Here, we report the use of metabolic glycan labeling to facilitate cancer-targeted delivery of liposomal chemoimmunotherapy. 4T1 triple-negative breast cancer cells can be metabolically labeled with azido groups for subsequently targeted conjugation of dibenzocycoloctyne (DBCO)-bearing liposomes loaded with doxorubicin and imiquimod (R837) adjuvant <i>via</i> efficient click chemistry. The encased doxorubicin can induce the immunogenic death of cancer cells and upregulate the expression of CD47 and calreticulin on the surface of cancer cells, while R837 can activate dendritic cells for enhanced processing and presentation of tumor antigens. Targeted delivery of liposomes encapsulating doxorubicin and R837 to 4T1 tumors, enabled by metabolic glycan labeling and click chemistry, showed the promise to reshape the immunosuppressive tumor microenvironment of solid tumors. This cancer-targetable liposomal chemoimmunotherapy could provide a new approach to improving conventional chemotherapy.
    Keywords:  chemo-immunotherapy; click chemistry; immunotherapy; liposome; metabolic glycan labeling
    DOI:  https://doi.org/10.3389/fimmu.2022.1010021
  5. Nat Commun. 2022 Nov 05. 13(1): 6681
    Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR.
    Emily Sempou, Valentyna Kostiuk, Jie Zhu, M Cecilia Guerra, Leonid Tyan, Woong Hwang, Elena Camacho-Aguilar, Michael J Caplan, David Zenisek, Aryeh Warmflash, Nick D L Owens, Mustafa K Khokha.
      Transitioning from pluripotency to differentiated cell fates is fundamental to both embryonic development and adult tissue homeostasis. Improving our understanding of this transition would facilitate our ability to manipulate pluripotent cells into tissues for therapeutic use. Here, we show that membrane voltage (Vm) regulates the exit from pluripotency and the onset of germ layer differentiation in the embryo, a process that affects both gastrulation and left-right patterning. By examining candidate genes of congenital heart disease and heterotaxy, we identify KCNH6, a member of the ether-a-go-go class of potassium channels that hyperpolarizes the Vm and thus limits the activation of voltage gated calcium channels, lowering intracellular calcium. In pluripotent embryonic cells, depletion of kcnh6 leads to membrane depolarization, elevation of intracellular calcium levels, and the maintenance of a pluripotent state at the expense of differentiation into ectodermal and myogenic lineages. Using high-resolution temporal transcriptome analysis, we identify the gene regulatory networks downstream of membrane depolarization and calcium signaling and discover that inhibition of the mTOR pathway transitions the pluripotent cell to a differentiated fate. By manipulating Vm using a suite of tools, we establish a bioelectric pathway that regulates pluripotency in vertebrates, including human embryonic stem cells.
    DOI:  https://doi.org/10.1038/s41467-022-34363-w
  6. Biomolecules. 2022 Oct 28. pii: 1581. [Epub ahead of print]12(11):
    Metabolism of Selenium, Selenocysteine, and Selenoproteins in Ferroptosis in Solid Tumor Cancers.
    Briana K Shimada, Sydonie Swanson, Pamela Toh, Lucia A Seale.
      A potential target of precision nutrition in cancer therapeutics is the micronutrient selenium (Se). Se is metabolized and incorporated as the amino acid selenocysteine (Sec) into 25 human selenoproteins, including glutathione peroxidases (GPXs) and thioredoxin reductases (TXNRDs), among others. Both the processes of Se and Sec metabolism for the production of selenoproteins and the action of selenoproteins are utilized by cancer cells from solid tumors as a protective mechanism against oxidative damage and to resist ferroptosis, an iron-dependent cell death mechanism. Protection against ferroptosis in cancer cells requires sustained production of the selenoprotein GPX4, which involves increasing the uptake of Se, potentially activating Se metabolic pathways such as the trans-selenation pathway and the TXNRD1-dependent decomposition of inorganic selenocompounds to sustain GPX4 synthesis. Additionally, endoplasmic reticulum-resident selenoproteins also affect apoptotic responses in the presence of selenocompounds. Selenoproteins may also help cancer cells adapting against increased oxidative damage and the challenges of a modified nutrient metabolism that result from the Warburg switch. Finally, cancer cells may also rewire the selenoprotein hierarchy and use Se-related machinery to prioritize selenoproteins that are essential to the adaptations against ferroptosis and oxidative damage. In this review, we discuss both the evidence and the gaps in knowledge on how cancer cells from solid tumors use Se, Sec, selenoproteins, and the Se-related machinery to promote their survival particularly via resistance to ferroptosis.
    Keywords:  cancer; ferroptosis; selenium; selenium metabolism; solid tumors
    DOI:  https://doi.org/10.3390/biom12111581
  7. Chem Biol Interact. 2022 Nov 05. pii: S0009-2797(22)00454-9. [Epub ahead of print]368 110249
    Inhibited transcription factor EB function induces reactive oxygen species overproduction to promote pyroptosis in cadmium-exposed renal tubular epithelial cells.
    Peng-Fei Dong, Zi-Fa Li, Cai-Yu Lian, Zhen-Yong Wang, Lin Wang.
      Pyroptosis is a pro-inflammatory type of cell death involved in the pathogenesis of multiple kidney diseases, while transcription factor EB (TFEB) is shown to be important for rescuing renal function. Cadmium (Cd) is an omnipresent toxic heavy metal with definite nephrotoxicity, but there is lacking of evidence regarding an interplay between TFEB activity and pyroptosis during Cd exposure. In this study, Cd-exposed NRK-52E cells were used to clarify this issue as an in vitro model of acute kidney injury. First, our results showed that Cd exposure evidently elevated the protein levels involved in pyroptosis, increased lactate dehydrogenase (LDH) release, and disrupted the cell membrane integrity, suggesting the occurrence of pyroptosis in NRK-52E cells. It is also shown that Cd induced a burst of reactive oxygen species (ROS) to mediate pyroptosis. Simultaneously, downregulated TFEB expression with its inhibited nuclear translocation was revealed in Cd-exposed NRK-52E cells. Further investigations have demonstrated that TFEB knockdown promoted Cd-induced ROS production to exacerbate the pyroptosis, while TFEB overexpression inhibited Cd-induced ROS production to alleviate the pyroptosis in NRK-52E cells. In summary, these findings demonstrate that Cd-inhibited TFEB function results in ROS overproduction to promote pyroptosis in NRK-52E cells, which provide new insight into the therapeutic targets for Cd-induced kidney diseases.
    Keywords:  Cadmium; Kidney diseases; Pyroptosis; Reactive oxygen species; Transcription factor EB
    DOI:  https://doi.org/10.1016/j.cbi.2022.110249
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