bims-cemest Biomed News
on Cell metabolism and stress
Issue of 2025–06–08
seven papers selected by
Jessica Rosarda, Uniformed Services University
  1. Cycloheximide resistant ribosomes reveal adaptive translation dynamics in C. elegans.
  2. 1-Deoxysphingolipids dysregulate membrane properties and cargo trafficking in the early secretory pathway.
  3. HSF1 remodels mitochondrial biogenesis and function in cancer cells via TIMM17A.
  4. Perturbations in L-serine metabolism regulates protein quality control through sensor of retrograde response pathway Rtg2 in S.cerevisae.
  5. Diabetes mellitus and the key role of endoplasmic reticulum stress in pancreatic β cells.
  6. Concerted transport and phosphorylation of diacylglycerol at ER-PM contact sites regulate phospholipid dynamics during stress.
  7. A guide to heat shock factors as multifunctional transcriptional regulators.
  1. bioRxiv. 2025 May 13. pii: 2025.05.07.652686. [Epub ahead of print]
    Cycloheximide resistant ribosomes reveal adaptive translation dynamics in C. elegans.
    Qiuxia Zhao, Blythe Bolton, Reed Rothe, Reiko Tachibana, Can Cenik, Elif Sarinay Cenik.
      Protein translation regulation is critical for cellular responses and development, yet how disruptions during the elongation stage shape these processes remains incompletely understood. Here, we identify and validate a single amino acid substitution (P55Q) in the ribosomal protein RPL-36A of Caenorhabditis elegans that confers complete resistance to high concentrations of the elongation inhibitor cycloheximide (CHX). Heterozygous animals carrying both wild-type RPL-36A and RPL-36A(P55Q) exhibit normal development but intermediate CHX resistance, indicating a partial dominant effect. Leveraging RPL-36A(P55Q) as a single-copy positive selection marker for CRISPR-based genome editing, we introduced targeted modifications into multiple ribosomal protein genes, confirming its broad utility for altering essential loci. In L4-stage heterozygotes, where CHX-sensitive and CHX-resistant ribosomes coexist, ribosome profiling revealed increased start-codon occupancy, suggesting early stalling of CHX sensitive ribosomes. Chronic CHX reduced ribosome collisions, evidenced by fewer disomes and unchanged codon distributions in monosomes. Surprisingly, prolonged elongation inhibition did not activate well characterized stress pathways-including ribosome quality control (RQC), the ribotoxic stress response (RSR), or the integrated stress response (ISR)-as indicated by absence of changes in RPS-10 ubiquitination, eIF2α phosphorylation, PMK-1 phosphorylation, or the transcriptional upregulation of ATF-4 target genes. Instead, RNA-normalized ribosome footprints revealed gene-specific changes in translation efficiency, with nucleolar and P granule components significantly decreased while oocyte development genes were increased. Consistent with these observations, we detected premature oogenesis in L4 animals, suggesting that partial translation elongation inhibition reshapes translation efficiency, to fine-tune developmental timing.
    DOI:  https://doi.org/10.1101/2025.05.07.652686
  2. bioRxiv. 2025 May 17. pii: 2025.05.13.652513. [Epub ahead of print]
    1-Deoxysphingolipids dysregulate membrane properties and cargo trafficking in the early secretory pathway.
    Yi-Ting Tsai, Nicolas-Frédéric Lipp, Olivia Seidel, Riya Varma, Aurelie Laguerre, Kristina Solorio-Kirpichyan, Adrian Wong, Roberto J Brea, Grace H McGregor, Thekla Cordes, Neal K Devaraj, Lars Kuerschner, Sonya Neal, Christian M Metallo, Itay Budin.
      1-Deoxysphingolipids are non-canonical sphingolipids linked to several diseases, but their cellular effects are poorly understood. Here, we utilize lipid chemical biology approaches to investigate the role of 1-deoxysphingolipid metabolism on the properties and functions of secretory membranes. We first applied organelle-specific bioorthogonal labeling to visualize the subcellular distribution of metabolically tagged 1-deoxysphingolipids in RPE-1 cells, observing that they are retained in the endoplasmic reticulum (ER). We found that 1-deoxysphingolipids can be transported by the non-vesicular transporter CERT in vitro but are retained at ER exit sites (ERES) in cells, suggesting that they do not efficiently sort into vesicular carriers. Cells expressing disease-associated variants of serine palmitoyl-CoA transferase (SPT) accumulated long-chain 1-deoxysphingolipids, which reduced ER membrane fluidity and enlarged ERES. We observed that the rates of membrane protein release from the ER were altered in response to mutant SPT expression, in a manner that was dependent on the cargo affinity for ordered or disordered membranes. We propose that dysregulation of sphingolipid metabolism alters secretory membrane properties, which can then modulate protein trafficking.
    DOI:  https://doi.org/10.1101/2025.05.13.652513
  3. bioRxiv. 2025 May 14. pii: 2025.05.12.653547. [Epub ahead of print]
    HSF1 remodels mitochondrial biogenesis and function in cancer cells via TIMM17A.
    Ngoc G T Nguyen, Hem Sapkota, Yoko Shibata, Aleksandra Fesiuk, Matthew Antalek, Vibhavari Sail, Daniel J Ansel, David R Amici, Frederick F Peelor, Holly Van Remmen, Benjamin F Miller, Marc L Mendillo, Richard I Morimoto, Jian Li.
      Mitochondria play critical roles in energy production and cellular metabolism. Despite the Warburg effect, mitochondria are crucial for the survival and proliferation of cancer cells. Heat Shock Factor 1 (HSF1), a key transcription factor in the cellular heat shock response, promotes malignancy and metastasis when aberrantly activated. To understand the multifaceted roles of HSF1 in cancer, we performed a genome-wide CRISPR screen to identify epistatic interactors of HSF1 in cancer cell proliferation. The verified interactors of HSF1 include those involved in DNA replication and repair, transcriptional and post-transcriptional gene expression, and mitochondrial functions. Specifically, we found that HSF1 promotes cell proliferation, mitochondrial biogenesis, respiration, and ATP production in a manner dependent on TIMM17A, a subunit of the inner membrane translocase. HSF1 upregulates the steady-state level of the short-lived TIMM17A protein via its direct target genes, HSPD1 and HSPE1, which encode subunits of the mitochondrial chaperonin complex and are responsible for protein refolding once imported into the matrix. The HSF1- HSPD1/HSPE1-TIMM17A axis remodels the mitochondrial proteome to promote mitochondrial translation and energy production, thereby supporting robust cell proliferation. Our work reveals a mechanism by which mitochondria adjust protein uptake according to the folding capacity in the matrix by altering TIM complex composition.
    DOI:  https://doi.org/10.1101/2025.05.12.653547
  4. J Biol Chem. 2025 May 31. pii: S0021-9258(25)02179-9. [Epub ahead of print] 110329
    Perturbations in L-serine metabolism regulates protein quality control through sensor of retrograde response pathway Rtg2 in S.cerevisae.
    Kanika Saxena, Rebecca Andersson, Per O Widlund, Sakda Khoomrung, Sarah Hanzén, Jens Nielsen, Navinder Kumar, Mikael Molin, Thomas Nyström.
      Cellular protein homeostasis relies on a complex network of protein synthesis, folding, sub-cellular localization, and degradation to sustain a functional proteome. Since, most of these processes are energy driven, proteostasis is inescapably afflicted by cellular metabolism. Proteostasis collapse and metabolic imbalance are both linked to aging and age-associated disorders, yet they have traditionally been studied as a separate phenomenon in the context of aging. In this study, we indicate that reduced proteostasis capacity is a result of a metabolic imbalance associated with age. We observed increased accumulation of L-serine and L-threonine in replicative old cells of S. cerevisiae, indicating an imbalance in amino acid metabolism with replicative aging. Replicating this metabolic imbalance in young cells through deletion of serine dependent transcriptional activator, CHA4, resulted in increased aggregation of endogenous proteins along with misfolding prone proteins Guk1-7ts-GFP and Luciferase-GFP in both young and old cells. Aggregate formation in the cha4Δ strain required a functional sensor of mitochondrial dysfunction and an activator of the retrograde signalling gene, RTG2. CHA4 and RTG2 exhibited genetic interaction and together regulated mitochondrial metabolism, replicative lifespan, and aggregate formation in young cells, connecting metabolic regulation with proteostasis and aging. Constitutive activation of retrograde signalling through overexpression of RTG2 or deletion of MKS-1, negative regulator of Rtg1-Rtg3 nuclear translocation, resulted in faster resolution of aggregates upon heat shock through RTG3 and was found to be independent of molecular chaperone upregulation.
    Keywords:  Aggregation; aging; mitochondria; proteostasis; replicative aging; retrograde response; serine
    DOI:  https://doi.org/10.1016/j.jbc.2025.110329
  5. Nat Rev Endocrinol. 2025 Jun 04.
    Diabetes mellitus and the key role of endoplasmic reticulum stress in pancreatic β cells.
    Maria Lytrivi, Yue Tong, Enrico Virgilio, Xiaoyan Yi, Miriam Cnop.
      Insufficient insulin secretion by pancreatic β cells is central to the pathogenesis of diabetes mellitus. As insulin is synthesized in the endoplasmic reticulum (ER), perturbations in ER homeostasis lead to ER stress and activate the ER stress response. Over the past two decades, considerable data have accumulated on the role of β cell ER stress in diabetes mellitus. Several monogenic forms of diabetes mellitus are caused by excessive ER stress, perturbed ER stress response signalling or impaired ER-Golgi protein trafficking. These pathways are now recognized to contribute to β cell failure in both type 1 and type 2 diabetes mellitus. This Review considers the role of β cell ER stress in common forms of diabetes mellitus and examines whether it is a cause or a consequence of these diseases. The strong genetic evidence for a causal role of ER stress in 15 monogenic forms of diabetes mellitus is summarized, and the effects of ER stress on human β cell differentiation, function and survival are described. Although definitive proof is lacking that ER stress responses can be therapeutically targeted to improve β cell function in diabetes mellitus, existing and novel treatments that aim to restore ER homeostasis are also outlined.
    DOI:  https://doi.org/10.1038/s41574-025-01129-5
  6. Proc Natl Acad Sci U S A. 2025 Jun 10. 122(23): e2421334122
    Concerted transport and phosphorylation of diacylglycerol at ER-PM contact sites regulate phospholipid dynamics during stress.
    Selene Garcia-Hernandez, Jorge Morello-López, Richard Haslam, Vitor Amorim-Silva, José Moya-Cuevas, Rafael Catalá, Louise Michaelson, Jessica Pérez-Sancho, Vedrana Marković, Julio Salinas, Johnathan Napier, Yvon Jaillais, Noemí Ruiz-Lopez, Miguel A Botella.
      A universal response of plants to environmental stresses is the activation of plasma membrane (PM) phospholipase C, which hydrolyzes phosphoinositides to produce soluble inositol phosphate and diacylglycerol (DAG). Because of their conical shape, DAG amounts have to be tightly regulated or they can destabilize membranes. We previously showed that upon stress, Synaptotagmin1 (SYT1) transports DAG from the PM to the endoplasmic reticulum (ER) at ER-PM Contact Sites (CS). Here, we addressed the fate of the incoming DAG in the ER. We show that diacylglycerol kinases (DGKs) DGK1 and DGK2 form a module with SYT1 functionally coupling DAG transport and phosphorylation at ER-PM CS. Although SYT1 and DGK1/DGK2 do not show exclusive ER-PM CS localization, their interaction occurs specifically at ER-PM CS and the removal of ER-PM CS abolishes the interaction. Lipidomic analysis of a dgk1dgk2 double mutant supports that DGK1 and DGK2 phosphorylate DAG at the ER and transcriptomic and phenotypic analyses indicate that SYT1 and DGK1/DGK2 are functionally related. Taken together, our results highlight a mechanism at ER-PM CS that coordinates the transfer of DAG from the PM to the ER by SYT1 upon stress and the concomitant phosphorylation of DAG by DGK1 and DGK2 at the ER. These findings underscore the critical role of spatial coordination in lipid metabolism during stress-induced membrane remodeling.
    Keywords:  DAG; PI cycle; abiotic stress; contact sites; signaling
    DOI:  https://doi.org/10.1073/pnas.2421334122
  7. FEBS J. 2025 Jun 02.
    A guide to heat shock factors as multifunctional transcriptional regulators.
    Hendrik S E Hästbacka, Alejandro J Da Silva, Lea Sistonen, Eva Henriksson.
      The heat shock factors (HSFs) form a family of transcription factors, which are evolutionarily conserved in eukaryotes. They are best known as transcriptional regulators of molecular chaperone genes, including those encoding heat shock proteins, in response to heat shock and other protein-damaging stresses. Since the discovery of the first HSF and its eponymous role in the heat shock response four decades ago, the currently known HSFs in vertebrates, that is, HSF1-5, HSFX, and HSFY, have been implicated in a wide array of physiological and pathological processes, including organismal development and cancer progression. To date, most studies have focused on individual HSFs, but it is becoming increasingly evident that the role of multiple HSFs and their potential crosstalk should be considered. In this review, we provide a comprehensive overview of the structures, functions, and regulation of the mammalian HSF family members and explore their interplay in biological processes. We highlight recent advancements regarding the roles of HSF family members in viral infection, cell adhesion, and spermatogenesis, and discuss the key questions to be addressed by forthcoming studies in HSF biology.
    Keywords:  HSE; HSF; HSP; HSR; adhesion; cancer; development; spermatogenesis; stress; transcription
    DOI:  https://doi.org/10.1111/febs.70139
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