bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2024‒02‒11
fourteen papers selected by
William Grey, University of York
  1. The GATOR2 complex maintains lysosomal-autophagic function by inhibiting the protein degradation of MiT/TFEs.
  2. Phosphatase, Mg2+/Mn2+ dependent 1B regulates the hematopoietic stem cells homeostasis via the Wnt/β-catenin signaling.
  3. SHP-1 inhibition targets leukaemia stem cells to restore immunosurveillance and enhance chemosensitivity by metabolic reprogramming.
  4. Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche.
  5. A feedback loop that drives cell death and proliferation and its defect in intestinal stem cells.
  6. Diffusible fraction of niche BMP ligand safeguards stem-cell differentiation.
  7. Quantification of local matrix deposition during muscle stem cell activation using engineered hydrogels.
  8. Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency.
  9. Navigating the landscape of mitochondrial-ER communication in health and disease.
  10. Paraoxonase-like APMAP maintains endoplasmic reticulum-associated lipid and lipoprotein homeostasis.
  11. Highly specific intracellular ubiquitination of a small molecule.
  12. Targeting AXL induces tumor-intrinsic immunogenic response in tyrosine kinase inhibitor-resistant liver cancer.
  13. Manipulating Redox Homeostasis of Cancer Stem Cells Overcome Chemotherapeutic Resistance through Photoactivatable Biomimetic Nanodiscs.
  14. Regulation of proteostasis and innate immunity via mitochondria-nuclear communication.
  1. Mol Cell. 2024 Jan 31. pii: S1097-2765(24)00048-0. [Epub ahead of print]
    The GATOR2 complex maintains lysosomal-autophagic function by inhibiting the protein degradation of MiT/TFEs.
    Shu Yang, Chun-Yuan Ting, Mary A Lilly.
      Lysosomes are central to metabolic homeostasis. The microphthalmia bHLH-LZ transcription factors (MiT/TFEs) family members MITF, TFEB, and TFE3 promote the transcription of lysosomal and autophagic genes and are often deregulated in cancer. Here, we show that the GATOR2 complex, an activator of the metabolic regulator TORC1, maintains lysosomal function by protecting MiT/TFEs from proteasomal degradation independent of TORC1, GATOR1, and the RAG GTPase. We determine that in GATOR2 knockout HeLa cells, members of the MiT/TFEs family are ubiquitylated by a trio of E3 ligases and are degraded, resulting in lysosome dysfunction. Additionally, we demonstrate that GATOR2 protects MiT/TFE proteins in pancreatic ductal adenocarcinoma and Xp11 translocation renal cell carcinoma, two cancers that are driven by MiT/TFE hyperactivation. In summary, we find that the GATOR2 complex has independent roles in TORC1 regulation and MiT/TFE protein protection and thus is central to coordinating cellular metabolism with control of the lysosomal-autophagic system.
    Keywords:  E3 ligases; GATOR2; MiT/TFEs; TORC1; autophagy; lysosome; pancreatic ductal adenocarcinoma; renal cell carcinoma; ubiquitination
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.012
  2. Haematologica. 2024 Feb 08.
    Phosphatase, Mg2+/Mn2+ dependent 1B regulates the hematopoietic stem cells homeostasis via the Wnt/β-catenin signaling.
    Zhiyuan Lu, Hanzhi Yu, Yanxia Li, Guangsen Xu, Xiaoxun Li, Yongjun Liu, Yuemao Shen, Zhigang Cai, Baobing Zhao.
      Hematopoietic stem cells (HSCs) are primarily dormant in a cell-cycle quiescence state to preserve their self-renewal capacity and long-term maintenance. How HSCs maintain the balance between activation and quiescence remains largely unknown. Herein, we found that Phosphatase, Mg2+/Mn2+ Dependent 1B (Ppm1b) is required for the expansion of phenotypic HSCs in vitro. By using a conditional knockout mouse model in which Ppm1b was specifically depleted in hematopoietic cells, we demonstrated that loss of Ppm1b impaired the HSC homeostasis and hematopoietic reconstitution. Ppm1b deficiency mice also exhibited B-cell leukocytopenia, which is due to the compromised commitment and proliferation of B-biased lymphoid progenitor cells from CLPs. With the aid of a small molecular inhibitor, we confirmed the roles of Ppm1b in adult hematopoiesis that phenocopied the effects with loss of Ppm1b. Furthermore, transcriptome profiling of Ppm1b-deficient HSCs revealed the disruptive quiescence of HSC. Mechanistically, Ppm1b interacted with β-catenin and mediated its dephosphorylation. Loss of Ppm1b led to the decrease of the active β- catenin (non-phosphorylated) that interrupted the Wnt/β-catenin signaling in HSC, which consequently suppressed HSC expansion. Together, our study identified an indispensable role of Ppm1b in regulating HSC homeostasis via Wnt/β-catenin pathway.
    DOI:  https://doi.org/10.3324/haematol.2023.284305
  3. Nat Cell Biol. 2024 Feb 06.
    SHP-1 inhibition targets leukaemia stem cells to restore immunosurveillance and enhance chemosensitivity by metabolic reprogramming.
    Xi Xu, Yanhui Yu, Wenwen Zhang, Weiwei Ma, Chong He, Guo Qiu, Xinyi Wang, Qiong Liu, Minyi Zhao, Jiayi Xie, Fang Tao, John M Perry, Qifa Liu, Shuan Rao, Xunlei Kang, Meng Zhao, Linjia Jiang.
      Leukaemia stem cells (LSCs) in acute myeloid leukaemia present a considerable treatment challenge due to their resistance to chemotherapy and immunosurveillance. The connection between these properties in LSCs remains poorly understood. Here we demonstrate that inhibition of tyrosine phosphatase SHP-1 in LSCs increases their glycolysis and oxidative phosphorylation, enhancing their sensitivity to chemotherapy and vulnerability to immunosurveillance. Mechanistically, SHP-1 inhibition leads to the upregulation of phosphofructokinase platelet (PFKP) through the AKT-β-catenin pathway. The increase in PFKP elevates energy metabolic activities and, as a consequence, enhances the sensitivity of LSCs to chemotherapeutic agents. Moreover, the upregulation of PFKP promotes MYC degradation and, consequently, reduces the immune evasion abilities of LSCs. Overall, our study demonstrates that targeting SHP-1 disrupts the metabolic balance in LSCs, thereby increasing their vulnerability to chemotherapy and immunosurveillance. This approach offers a promising strategy to overcome LSC resistance in acute myeloid leukaemia.
    DOI:  https://doi.org/10.1038/s41556-024-01349-3
  4. Nat Commun. 2024 Feb 05. 15(1): 1090
    Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche.
    Amy Dawson, Martha M Zarou, Bodhayan Prasad, Joana Bittencourt-Silvestre, Désirée Zerbst, Ekaterini Himonas, Ya-Ching Hsieh, Isabel van Loon, Giovanny Rodriguez Blanco, Angela Ianniciello, Zsombor Kerekes, Vaidehi Krishnan, Puneet Agarwal, Hassan Almasoudi, Laura McCluskey, Lisa E M Hopcroft, Mary T Scott, Pablo Baquero, Karen Dunn, David Vetrie, Mhairi Copland, Ravi Bhatia, Seth B Coffelt, Ong Sin Tiong, Helen Wheadon, Sara Zanivan, Kristina Kirschner, G Vignir Helgason.
      Macrophages are fundamental cells of the innate immune system that support normal haematopoiesis and play roles in both anti-cancer immunity and tumour progression. Here we use a chimeric mouse model of chronic myeloid leukaemia (CML) and human bone marrow (BM) derived macrophages to study the impact of the dysregulated BM microenvironment on bystander macrophages. Utilising single-cell RNA sequencing (scRNA-seq) of Philadelphia chromosome (Ph) negative macrophages we reveal unique subpopulations of immature macrophages residing in the CML BM microenvironment. CML exposed macrophages separate from their normal counterparts by reduced expression of the surface marker CD36, which significantly reduces clearance of apoptotic cells. We uncover aberrant production of CML-secreted factors, including the immune modulatory protein lactotransferrin (LTF), that suppresses efferocytosis, phagocytosis, and CD36 surface expression in BM macrophages, indicating that the elevated secretion of LTF is, at least partially responsible for the supressed clearance function of Ph- macrophages.
    DOI:  https://doi.org/10.1038/s41467-024-45471-0
  5. Life Sci Alliance. 2024 Apr;pii: e202302238. [Epub ahead of print]7(4):
    A feedback loop that drives cell death and proliferation and its defect in intestinal stem cells.
    Shivakshi Sulekh, Yuko Ikegawa, Saki Naito, Asami Oji, Ichiro Hiratani, Sa Kan Yoo.
      Cell death and proliferation are at a glance dichotomic events, but occasionally coupled. Caspases, traditionally known to execute apoptosis, play non-apoptotic roles, but their exact mechanism remains elusive. Here, using Drosophila intestinal stem cells (ISCs), we discovered that activation of caspases induces massive cell proliferation rather than cell death. We elucidate that a positive feedback circuit exists between caspases and JNK, which can simultaneously drive cell proliferation and cell death. In ISCs, signalling from JNK to caspases is defective, which skews the balance towards proliferation. Mechanistically, two-tiered regulation of the DIAP1 inhibitor rpr, through its transcription and its protein localization, exists. This work provides a conceptual framework that explains how caspases perform apoptotic and non-apoptotic functions in vivo and how ISCs accomplish their resistance to cell death.
    DOI:  https://doi.org/10.26508/lsa.202302238
  6. Nat Commun. 2024 Feb 07. 15(1): 1166
    Diffusible fraction of niche BMP ligand safeguards stem-cell differentiation.
    Sharif M Ridwan, Autumn Twillie, Samaneh Poursaeid, Emma Kristine Beard, Muhammed Burak Bener, Matthew Antel, Ann E Cowan, Shinya Matsuda, Mayu Inaba.
      Drosophila male germline stem cells (GSCs) reside at the tip of the testis and surround a cluster of niche cells. Decapentaplegic (Dpp) is one of the well-established ligands and has a major role in maintaining stem cells located in close proximity. However, the existence and the role of the diffusible fraction of Dpp outside of the niche have been unclear. Here, using genetically-encoded nanobodies called Morphotraps, we physically block Dpp diffusion without interfering with niche-stem cell signaling and find that a diffusible fraction of Dpp is required to ensure differentiation of GSC daughter cells, opposite of its role in maintenance of GSC in the niche. Our work provides an example in which a soluble niche ligand induces opposed cellular responses in stem cells versus in differentiating descendants to ensure spatial control of the niche. This may be a common mechanism to regulate tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41467-024-45408-7
  7. bioRxiv. 2024 Jan 23. pii: 2024.01.20.576326. [Epub ahead of print]
    Quantification of local matrix deposition during muscle stem cell activation using engineered hydrogels.
    Pamela Duran, Benjamin A Yang, Eleanor Plaster, Madeline Eiken, Claudia Loebel, Carlos A Aguilar.
      Adult stem cells occupy a niche that contributes to their function, but how stem cells remodel their microenvironment remains an open-ended question. Herein, biomaterials-based systems and metabolic labeling were utilized to evaluate how skeletal muscle stem cells deposit extracellular matrix. Muscle stem cells and committed myoblasts were observed to generate less nascent matrix than muscle resident fibro-adipogenic progenitors. When cultured on substrates that matched the stiffness of physiological uninjured and injured muscles, the increased nascent matrix deposition was associated with stem cell activation. Reducing the ability to deposit nascent matrix in muscle stem cells attenuated function and mimicked impairments observed from muscle stem cells isolated from old aged muscles, which could be rescued with therapeutic supplementation of insulin-like growth factors. These results highlight how nascent matrix production is critical for maintaining healthy stem cell function.
    DOI:  https://doi.org/10.1101/2024.01.20.576326
  8. Hum Mol Genet. 2024 Feb 07. pii: ddae018. [Epub ahead of print]
    Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency.
    Vanitha Nithianandam, Souvarish Sarkar, Mel B Feany.
      Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number of mitochondrial genes, including electron transport chain components, in a large forward genetic screen for mutations causing age-related neurodegeneration in the context of proteostasis dysfunction. We created a model of complex I deficiency in the Drosophila retina to probe the role of protein degradation abnormalities in mitochondrial encephalomyopathies. Using our genetic model, we found that complex I deficiency regulates both the ubiquitin/proteasome and autophagy/lysosome arms of the proteostasis machinery. We further performed an in vivo kinome screen to uncover new and potentially druggable mechanisms contributing to complex I related neurodegeneration and proteostasis failure. Reduction of RIOK kinases and the innate immune signaling kinase pelle prevented neurodegeneration in complex I deficiency animals. Genetically targeting oxidative stress, but not RIOK1 or pelle knockdown, normalized proteostasis markers. Our findings outline distinct pathways controlling neurodegeneration and protein degradation in complex I deficiency and introduce an experimentally facile model in which to study these debilitating and currently treatment-refractory disorders.
    Keywords:  Drosophila; complex I deficiency; mitochondria; neurotoxicity; proteostasis
    DOI:  https://doi.org/10.1093/hmg/ddae018
  9. Front Mol Biosci. 2024 ;11 1356500
    Navigating the landscape of mitochondrial-ER communication in health and disease.
    Conor T Ronayne, Pedro Latorre-Muro.
      Intracellular organelle communication enables the maintenance of tissue homeostasis and health through synchronized adaptive processes triggered by environmental cues. Mitochondrial-Endoplasmic Reticulum (ER) communication sustains cellular fitness by adjusting protein synthesis and degradation, and metabolite and protein trafficking through organelle membranes. Mitochondrial-ER communication is bidirectional and requires that the ER-components of the Integrated Stress Response signal to mitochondria upon activation and, likewise, mitochondria signal to the ER under conditions of metabolite and protein overload to maintain proper functionality and ensure cellular survival. Declines in the mitochondrial-ER communication occur upon ageing and correlate with the onset of a myriad of heterogeneous age-related diseases such as obesity, type 2 diabetes, cancer, or neurodegenerative pathologies. Thus, the exploration of the molecular mechanisms of mitochondrial-ER signaling and regulation will provide insights into the most fundamental cellular adaptive processes with important therapeutical opportunities. In this review, we will discuss the pathways and mechanisms of mitochondrial-ER communication at the mitochondrial-ER interface and their implications in health and disease.
    Keywords:  calcium signaling; cellular fitness; endoplasmic reticulum; lipid trafficking; mitochondria; mitochondrial-ER communication; protein homeostasis; unfolded protein response
    DOI:  https://doi.org/10.3389/fmolb.2024.1356500
  10. bioRxiv. 2024 Jan 27. pii: 2024.01.26.577049. [Epub ahead of print]
    Paraoxonase-like APMAP maintains endoplasmic reticulum-associated lipid and lipoprotein homeostasis.
    Blessy Paul, Holly Merta, Rupali Ugrankar-Banerjee, Monica Hensley, Son Tran, Goncalo Dias do Vale, Jeffrey G McDonald, Steven A Farber, W Mike Henne.
      Oxidative stress perturbs lipid homeostasis and contributes to metabolic diseases. Though ignored compared to mitochondrial oxidation, the endoplasmic reticulum (ER) generates reactive oxygen species requiring antioxidant quality control. Using multi-organismal profiling featuring Drosophila , zebrafish, and mammalian cells, here we characterize the paraoxonase-like APMAP as an ER-localized protein that promotes redox and lipid homeostasis and lipoprotein maturation. APMAP-depleted mammalian cells exhibit defective ER morphology, elevated ER and oxidative stress, lipid droplet accumulation, and perturbed ApoB-lipoprotein homeostasis. Critically, APMAP loss is rescued with chemical antioxidant NAC. Organismal APMAP depletion in Drosophila perturbs fat and lipoprotein homeostasis, and zebrafish display increased vascular ApoB-containing lipoproteins, particles that are atherogenic in mammals. Lipidomics reveals altered polyunsaturated phospholipids and increased ceramides upon APMAP loss, which perturbs ApoB-lipoprotein maturation. These ApoB-associated defects are rescued by inhibiting ceramide synthesis. Collectively, we propose APMAP is an ER-localized antioxidant that promotes lipid and lipoprotein homeostasis.Key findings summary: APMAP localizes primarily to the ER network in human cells and Drosophila fat body tissue, and is a type II integral membrane protein Loss of APMAP or Drosophila APMAP (dAPMAP) causes ER membrane expansion, elevates CHOP-associated ER stress, promotes LD accumulation, and alters ApoB-lipoprotein secretion APMAP-depleted cells and dAPMAP-depleted Drosophila fat tissue exhibit defective redox homeostasis; phenotypes associated with APMAP loss are rescued by antioxidant NAC Zebrafish-based LipoGlo reporter reveals that loss of apmap in zebrafish causes increased vascular ApoB-containing lipoproteins Lipidomic profiling indicates that APMAP loss reduces PUFA-phospholipids and elevates intracellular ceramides, which perturbs ApoB maturation.
    DOI:  https://doi.org/10.1101/2024.01.26.577049
  11. bioRxiv. 2024 Jan 28. pii: 2024.01.26.577493. [Epub ahead of print]
    Highly specific intracellular ubiquitination of a small molecule.
    Weicheng Li, Enrique M Garcia-Rivera, Dylan C Mitchell, Joel M Chick, Micah Maetani, John M Knapp, Geoffrey M Matthews, Ryosuke Shirasaki, Ricardo de Matos Simoes, Vasanthi Viswanathan, John L Pulice, Matthew G Rees, Jennifer A Roth, Steven P Gygi, Constantine S Mitsiades, Cigall Kadoch, Stuart L Schreiber, Jonathan M L Ostrem.
      Ubiquitin is a small, highly conserved protein that acts as a posttranslational modification in eukaryotes. Ubiquitination of proteins frequently serves as a degradation signal, marking them for disposal by the proteasome. Here, we report a novel small molecule from a diversity-oriented synthesis library, BRD1732, that is directly ubiquitinated in cells, resulting in dramatic accumulation of inactive ubiquitin monomers and polyubiquitin chains causing broad inhibition of the ubiquitin-proteasome system. Ubiquitination of BRD1732 and its associated cytotoxicity are stereospecific and dependent upon two homologous E3 ubiquitin ligases, RNF19A and RNF19B. Our finding opens the possibility for indirect ubiquitination of a target through a ubiquitinated bifunctional small molecule, and more broadly raises the potential for posttranslational modification in trans .
    DOI:  https://doi.org/10.1101/2024.01.26.577493
  12. Cell Death Dis. 2024 Feb 03. 15(2): 110
    Targeting AXL induces tumor-intrinsic immunogenic response in tyrosine kinase inhibitor-resistant liver cancer.
    Yunong Xie, Haofeng Wu, Yimiao He, Linglin Liu, Ianto Bosheng Huang, Lei Zhou, Cheuk-Yin Lin, Rainbow Wing-Hei Leung, Jia-Jian Loh, Terence Kin-Wah Lee, Jin Ding, Kwan Man, Stephanie Ma, Man Tong.
      Hepatocellular carcinoma (HCC) is an aggressive malignancy without effective therapeutic approaches. Here, we evaluate the tumor-intrinsic mechanisms that attenuate the efficacy of immune checkpoint inhibitor (ICI) that is observed in patients with advanced HCC who progress on first-line tyrosine kinase inhibitor (TKI) therapy. Upregulation of AXL observed in sorafenib- and lenvatinib-resistant HCCs is correlated with poor response towards TKI and ICI treatments. AXL upregulation protects sorafenib-resistant HCC cells from oxidative stress, mitochondrial damage, and accompanying immunogenic cell death through suppressed tumor necrosis factor-α (TNF-α) and STING-type I interferon pathways. Pharmacological inhibition of AXL abrogates the protective effect and re-sensitizes TKI-resistant HCC tumors to anti-PD-1 treatment. We suggest that targeting AXL in combination with anti-PD-1 may provide an alternative treatment scheme for HCC patients who progress on TKI treatment.
    DOI:  https://doi.org/10.1038/s41419-024-06493-0
  13. Small. 2024 Feb 07. e2308539
    Manipulating Redox Homeostasis of Cancer Stem Cells Overcome Chemotherapeutic Resistance through Photoactivatable Biomimetic Nanodiscs.
    Bo Wang, Wuwan Wang, Yunxue Xu, Renfa Liu, Rui Li, Peipei Yang, Chenyang Zhao, Zhifei Dai, Yong Wang.
      Tumor heterogeneity remains a significant obstacle in cancer therapy due to diverse cells with varying treatment responses. Cancer stem-like cells (CSCs) contribute significantly to intratumor heterogeneity, characterized by high tumorigenicity and chemoresistance. CSCs reside in the depth of the tumor, possessing low reactive oxygen species (ROS) levels and robust antioxidant defense systems to maintain self-renewal and stemness. A nanotherapeutic strategy is developed using tumor-penetrating peptide iRGD-modified high-density lipoprotein (HDL)-mimetic nanodiscs (IPCND) that ingeniously loaded with pyropheophorbide-a (Ppa), bis (2-hydroxyethyl) disulfide (S-S), and camptothecin (CPT) by synthesizing two amphiphilic drug-conjugated sphingomyelin derivatives. Photoactivatable Ppa can generate massive ROS which as intracellular signaling molecules effectively shut down self-renewal and trigger differentiation of the CSCs, while S-S is utilized to deplete GSH and sustainably imbalance redox homeostasis by reducing ROS clearance. Simultaneously, the depletion of GSH is accompanied by the release of CPT, which leads to subsequent cell death. This dual strategy successfully disturbed the redox equilibrium of CSCs, prompting their differentiation and boosting the ability of CPT to kill CSCs upon laser irradiation. Additionally, it demonstrated a synergistic anti-cancer effect by concurrently eliminating therapeutically resistant CSCs and bulk tumor cells, effectively suppressing tumor growth in CSC-enriched heterogeneous colon tumor mouse models.
    Keywords:  cancer stem cells; chemotherapy; nanodiscs; photodynamic; tumor heterogeneity
    DOI:  https://doi.org/10.1002/smll.202308539
  14. J Cell Biol. 2024 Mar 04. pii: e202310005. [Epub ahead of print]223(3):
    Regulation of proteostasis and innate immunity via mitochondria-nuclear communication.
    Sookyung Kim, Theresa R Ramalho, Cole M Haynes.
      Mitochondria are perhaps best known as the "powerhouse of the cell" for their role in ATP production required for numerous cellular activities. Mitochondria have emerged as an important signaling organelle. Here, we first focus on signaling pathways mediated by mitochondria-nuclear communication that promote protein homeostasis (proteostasis). We examine the mitochondrial unfolded protein response (UPRmt) in C. elegans, which is regulated by a transcription factor harboring both a mitochondrial- and nuclear-targeting sequence, the integrated stress response in mammals, as well as the regulation of chromatin by mitochondrial metabolites. In the second section, we explore the role of mitochondria-to-nuclear communication in the regulation of innate immunity and inflammation. Perhaps related to their prokaryotic origin, mitochondria harbor molecules also found in viruses and bacteria. If these molecules accumulate in the cytosol, they elicit the same innate immune responses as viral or bacterial infection.
    DOI:  https://doi.org/10.1083/jcb.202310005
This page is being maintained by Thomas Krichel. It was last updated on 2024‒02‒11 at 6:56.