bims-cemest Biomed News
on Cell metabolism and stress
Issue of 2025–05–04
eight papers selected by
Jessica Rosarda, Uniformed Services University
  1. Regulation of translation elongation and integrated stress response in heat-shocked neurons.
  2. Feedback-responsive cell factories for dynamic modulation of the unfolded protein response.
  3. Structural basis for substrate selectivity by site-one protease revealed by studies with a small-molecule inhibitor.
  4. The Hsp90β Isoform: An Attractive Target for Drug Development.
  5. The link between the trans-Golgi network and tumour progression.
  6. Lipid metabolism alterations in peripheral neuropathies.
  7. Activation of the endoplasmic reticulum stress regulator IRE1α compromises pulmonary host defenses.
  8. Drosophila Clu ribonucleoprotein particle dynamics rely on the availability of functional Clu and translating ribosomes.
  1. Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00410-3. [Epub ahead of print]44(5): 115639
    Regulation of translation elongation and integrated stress response in heat-shocked neurons.
    Caitlin M Seluzicki, Milad Razavi-Mohseni, Fulya Türker, Priyal Patel, Boyang Hua, Michael A Beer, Loyal Goff, Seth S Margolis.
      Neurons deviate from a canonical heat shock response (HSR). Here, we revealed that neuronal adaptation to heat shock accompanies a brake on mRNA translation, slowed elongating ribosomes, phosphorylation of eukaryotic elongation factor-2 (p-eEF2), and suppressed the integrated stress response (ISR). Returning neurons to control temperature within 1 h of starting heat shock was necessary for survival and allowed for restored translation following dephosphorylation of eEF2. Subsequent to recovery, neurons briefly activated the ISR and were sensitive to the ISR inhibitor ISRIB, which enhanced protein synthesis and survival. Ribosome profiling and RNA sequencing (RNA-seq) identified newly synthesized and existing transcripts associated with ribosomes during heat shock. Preservation of these transcripts for translation during recovery was in part mediated by p-eEF2 and slowed ribosomes. Our work supports a neuronal heat shock model of a partially suspended state of translation poised for rapid reversal if recovery becomes an option and provides insight into regulation between the HSR and the ISR.
    Keywords:  CP: Molecular biology; CP: Neuroscience; ISR; eEF2; eIF2α; elongation; heat shock; integrated stress response; neurons; translation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115639
  2. Nat Commun. 2025 May 02. 16(1): 4106
    Feedback-responsive cell factories for dynamic modulation of the unfolded protein response.
    Daniela Barrios, Bhagyashree Bachhav, Wendolyn Carlos-Alcalde, Carlos D Llanos, Wenchang Zhou, Laura Segatori.
      Engineering cell factories that support the production of large quantities of protein therapeutics remains a significant biomanufacturing challenge. The overexpression of secretory proteins causes proteotoxic stress, affecting cell viability and protein productivity. Proteotoxic stress leads to the activation of the Unfolded Protein Response (UPR), a series of signal transduction pathways regulating protein quality control mechanisms aimed at restoring homeostasis. Sustained UPR activation culminates with the induction of apoptosis. Current strategies for enhancing the production of therapeutic proteins have focused on the deregulated modulation of key components of the UPR. These strategies have resulted in limited and often protein-specific improvements as they may lead to adaptation and cell toxicity and do not account for natural population heterogeneities. We report here feedback-responsive cell factories that sense proteotoxic stress and, in response, modulate the UPR to enhance stress attenuation and delay cell death, addressing the limitations of current strategies. We demonstrate that our cell engineering approach enables dynamic UPR modulation upon proteotoxic stress. The sense-and-respond systems that mediate dynamic UPR modulation enhance the production of the therapeutic enzyme tissue plasminogen activator and the bispecific antibody blinatumomab. Our feedback-responsive cell factories provide an innovative strategy for dynamically adjusting the innate cellular stress response and enhancing therapeutic protein manufacturing.
    DOI:  https://doi.org/10.1038/s41467-025-58994-x
  3. Proc Natl Acad Sci U S A. 2025 May 06. 122(18): e2426931122
    Structural basis for substrate selectivity by site-one protease revealed by studies with a small-molecule inhibitor.
    Ashley V Bullington, Ilaria Micallo, Bilkish Bajaj, Pankaj Kumar, Netanya Schlamowitz, Aurora Silva, Sebastian Hendrix, Noam Zelcer, Daniel L Kober.
      Site-one protease (S1P) carries out the first proteolytic step to activate membrane-bound effector proteins in the Golgi. S1P matures through an autocatalytic process that begins in the endoplasmic reticulum (ER) and culminates with the displacement of its inhibitory pro-domain by its cofactor, sterol regulatory element binding protein-regulating gene (SPRING). Spatial control of S1P activity and substrate localization underpins signaling pathways governing, among others, lipogenesis, ER stress, and lysosome biogenesis. The factors governing these pathways are activated by S1P-mediated proteolysis upon their regulated transport from the ER to the Golgi. S1P cleaves substrates with the recognition sequence RX(L/I/V)Z, where X is any residue other than Cys or Pro and Z is preferably Leu or Lys. However, the structural basis for substrate recognition by S1P has remained unknown. Here, we used the small molecule PF-429242, a competitive inhibitor of S1P, to investigate substrate recognition by the S1P/SPRING complex. We determined the structure of S1P/SPRING bound to PF-429242 and found that PF-429242 binds S1P in the same pocket that recognizes the substrate's conserved P4 Arg. Further structural analysis suggests that S1P requires a conformation change to accommodate the substrate's P2 (L/I/V) residue. We designed an S1P mutation (I308A) to reduce the steric clash at the P2 position and generated an S1P that was resistant to PF-429242 in biochemical and cell culture assays. Our findings reveal selectivity in the recognition of substrates by S1P and provide a roadmap for the rational design of improved S1P inhibitors.
    Keywords:  SPRING; cholesterol; cryo-EM; proteases; site-1-protease
    DOI:  https://doi.org/10.1073/pnas.2426931122
  4. Med Res Rev. 2025 Apr 28.
    The Hsp90β Isoform: An Attractive Target for Drug Development.
    Subhabrata Chaudhury, Terin D'Amico, Brian S J Blagg.
      The beta isoform of 90 kDa heat shock protein (Hsp90β) plays a critical role in maintaining cellular proteostasis by assisting in the folding and refolding of proteins, which is essential for both normal cellular function and stress response. It is constitutively expressed in mammalian cells, differentiating it from the inducible Hsp90α isoform. Hsp90β's involvement in diverse cellular processes, such as signal transduction, cell cycle control, and apoptosis, underscores its significant role in various diseases, including cancer and neurodegenerative disorders. The isoform-specific functions of Hsp90β and its interaction with unique client proteins make it a promising target for therapeutic intervention, particularly in the development of selective inhibitors that avoid the adverse effects observed with pan-Hsp90 inhibitors. This review delves into the structural and functional intricacies of Hsp90β, its role in disease, and the potential for selective drug development.
    Keywords:  Hsp90 beta; drug discovery; isoform selectivity; structure‐based drug design
    DOI:  https://doi.org/10.1002/med.22114
  5. Mol Biol Rep. 2025 Apr 28. 52(1): 435
    The link between the trans-Golgi network and tumour progression.
    Leila Jahangiri.
      The trans-Golgi network is a major sorting organelle consisting of a tubular membrane originating from the trans-Golgi cisternae. Proteins and lipids synthesised in the endoplasmic reticulum are transported through the Golgi apparatus and sorted in the trans-Golgi network into pleomorphic transport carriers targeted for various destinations. These destinations include the apical and basolateral membranes, early and late, recycling endosomes, and secretory granules. The trans-Golgi network also accepts retrograde endosome traffic, contributing to the recycling of proteins and lipids, and, therefore, sits at the crossroads of secretory and endosomal systems. Cancer is a somatic evolutionary process that comprises the accumulation of mutations that contribute to tumourigenesis, growth, progression, immune evasion, and resistance to therapy. This study aims to catalogue how multiple components and players of the trans-Golgi network affect tumour progression. Further, the link between the tumour microenvironment, the trans-Golgi network, and tumour progression will be dissected. A more profound understanding of these mechanisms will inform better treatment options.
    Keywords:  Endosomes; Progression; Trafficking; Trans-Golgi network; Tumour
    DOI:  https://doi.org/10.1007/s11033-025-10548-6
  6. Neuron. 2025 Apr 29. pii: S0896-6273(25)00262-4. [Epub ahead of print]
    Lipid metabolism alterations in peripheral neuropathies.
    Alessio Silva, Robert Prior, Maurizio D'Antonio, Johannes V Swinnen, Ludo Van Den Bosch.
      Alterations in lipid metabolism are increasingly recognized as central pathological hallmarks of inherited and acquired peripheral neuropathies. Correct lipid balance is critical for cellular homeostasis. However, the mechanisms linking lipid disturbances to cellular dysfunction and whether these changes are primary drivers or secondary effects of disease remain unresolved. This is particularly relevant in the peripheral nervous system, where the lipid-rich myelin integrity is critical for axonal function, and even subtle perturbations can cause widespread effects. This review explores the role of lipids as structural components as well as signaling molecules, emphasizing their metabolic role in peripheral neurons and Schwann cells. Additionally, we explore the genetic and environmental connections in both inherited and acquired peripheral neuropathies, respectively, which are known to affect lipid metabolism in peripheral neurons or Schwann cells. Overall, we highlight how understanding lipid-centric mechanisms could advance biomarker discovery and therapeutic interventions for peripheral nerve disorders.
    Keywords:  Charcot-Marie-Tooth disease; Schwann cells; lipid metabolism; lipid rafts; lipid signaling; lipid storage; motor neurons; peripheral neuropathies; sensory neurons
    DOI:  https://doi.org/10.1016/j.neuron.2025.04.006
  7. Cell Rep. 2025 Apr 30. pii: S2211-1247(25)00403-6. [Epub ahead of print]44(5): 115632
    Activation of the endoplasmic reticulum stress regulator IRE1α compromises pulmonary host defenses.
    Amit Sharma, Linda M Heffernan, Ky Hoang, Samithamby Jeyaseelan, William N Beavers, Basel H Abuaita.
      The endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) is associated with lung infections where innate immune cells are drivers for progression and resolution ammatory cytokinesflammation. Yet, the role of IRE1α in pulmonary innate immune host defense during acute respiratory infection remains unexplored. Here, we found that activation of IRE1α in infected lungs compromises immunity against methicillin-resistant Staphylococcus aureus (MRSA)-induced primary and secondary pneumonia. Moreover, activation of IRE1α in MRSA-infected lungs and alveolar macrophages (AMs) leads to exacerbated production of inflammatory mediators followed by cell death. Ablation of myeloid IRE1α or global IRE1α inhibition confers protection against MRSA-induced pneumonia with improved survival, bacterial clearance, cytokine reduction, and lung injury. In addition, loss of myeloid IRE1α protects mice against MRSA-induced secondary to influenza pneumonia by promoting AM survival. Thus, activation of IRE1α is detrimental to pneumonia, and therefore, it shows potential as a target to control excessive unresolved lung inflammation.
    Keywords:  CP: Immunology; Eicosanoids; GBPs; PR8; Type II interferons; UPR; USA300
    DOI:  https://doi.org/10.1016/j.celrep.2025.115632
  8. J Cell Sci. 2025 Apr 30. pii: jcs.263730. [Epub ahead of print]
    Drosophila Clu ribonucleoprotein particle dynamics rely on the availability of functional Clu and translating ribosomes.
    Hye Jin Hwang, Kelsey M Sheard, Rachel T Cox.
      Drosophila Clu is a conserved multi-domain ribonucleoprotein essential for mitochondrial function that forms dynamic particles within the cytoplasm. Unlike stress granules and Processing bodies, Clu particles disassemble under nutritional or oxidative stress. However, it is unclear how disrupting protein synthesis affects Clu particle dynamics, especially since Clu binds mRNA and ribosomes. Here, we capitalize on ex vivo and in vivo imaging of Drosophila female germ cells to determine what domains of Clu are necessary for Clu particle assembly and how manipulating translation affects particle dynamics. Using domain deletion analysis, we identified three domains of Clu, essential for particle assembly. We also demonstrated that overexpressing functional Clu disassembled particles. In addition, we inhibited translation using cycloheximide and puromycin. In contrast to Processing bodies, cycloheximide treatment did not disassemble Clu particles yet puromycin treatment did. Surprisingly, cycloheximide stabilized particles under oxidative and nutritional stress. These findings demonstrate that Clu particles display novel dynamics in response to altered ribosome activity and support a model where they function as translation hubs whose assembly heavily depends on the dynamic availability of translating ribosomes.
    Keywords:  Clu; Cycloheximide; Drosophila; Mitochondria; Ribonucleoprotein; Translation
    DOI:  https://doi.org/10.1242/jcs.263730
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