PLoS Biology最新文献

{"title":"Vps34-orchestrated lipid signaling processes regulate the transitional heterogeneity and functional adaptation of effector regulatory T cells.","authors":"Erienne G Norton, Nicole M Chapman, Hao Shi, Xiaoxi Meng, Hongling Huang, Anil Kc, Sherri Rankin, Jordy Saravia, Sujing Yuan, Haoran Hu, Peter Vogel, Hongbo Chi","doi":"10.1371/journal.pbio.3003074","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003074","url":null,"abstract":"<p><p>Regulatory T cell (Treg) heterogeneity exists in lymphoid and non-lymphoid tissues, but we have limited understanding of context-dependent functions and spatiotemporal regulators of heterogenous Treg states, especially during perinatal life when immune tolerance is established. Here, we revealed that the class III PI3K Vps34 orchestrates effector Treg (eTreg) transitional heterogeneity during perinatal life. We found that loss of Vps34 reduced terminal eTreg accumulation in lymphoid tissues, associated with decreased Treg generation in non-lymphoid tissues and development of an early-onset autoimmune-like disease. After perinatal life, Vps34-deficient eTreg accumulation was further impaired due to reduced cell survival, highlighting temporal regulation of eTreg heterogeneity and maintenance by Vps34. Accordingly, inhibition of Vps34 in mature Tregs disrupted immune homeostasis but boosted anti-tumor immunity. Mechanistically, multiomics profiling approaches uncovered that Vps34-orchestrated transcriptional and epigenetic remodeling promotes terminal eTreg programming. Further, via genetic deletion of the Vps34-interacting proteins Atg14 or Uvrag in Tregs, we established that Atg14 but not Uvrag was required for the overall survival, but not terminal differentiation, of eTregs, suggesting that autophagy but not endocytosis partly contributed to Vps34-dependent effects. Accordingly, mice with Treg-specific loss of Atg14, but not Uvrag, had moderately disrupted immune homeostasis and reduced tumor growth, with Vps34- or Atg14-dependent gene signatures also being elevated in intratumoral Tregs from human cancer patients. Collectively, our study reveals distinct Vps34-orchestrated signaling events that regulate eTreg heterogeneity and functional adaptation and the pathophysiological consequences on autoimmunity versus anti-tumor immunity.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003074"},"PeriodicalIF":9.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11990774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interferon regulatory factor 4 mediates nonenzymatic IRE1 dependency in multiple myeloma cells.","authors":"Ioanna Oikonomidi, Vasumathi Kameswaran, Victoria C Pham, Iratxe Zuazo-Gaztelu, Lauren M Gutgesell, Scot Marsters, Bence Daniel, Jennie R Lill, Zora Modrusan, Avi Ashkenazi","doi":"10.1371/journal.pbio.3003096","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003096","url":null,"abstract":"<p><p>Multiple myeloma (MM) arises through oncogenic transformation of immunoglobulin-secreting plasma cells. MM often co-opts the central endoplasmic reticulum (ER)-stress mitigator, inositol-requiring enzyme 1 (IRE1), to sustain malignant growth. While certain MMs require enzymatic IRE1-dependent activation of the transcription factor XBP1s, others display a nonenzymatic IRE1 dependency that is not yet mechanistically understood. Here we identify interferon regulatory factor 4 (IRF4), which stimulates genes that promote immune-cell proliferation, as a key conduit for IRE1's nonenzymatic control of cell-cycle progression in MM. IRE1 silencing increased inhibitory S114/S270 phosphorylation on IRF4, disrupting IRF4's chromatin-binding and transcriptional activity. IRF4 knockdown recapitulated, whereas IRF4 repletion reversed, the anti-proliferative phenotype of IRE1 silencing. Furthermore, phospho-deficient, but not phospho-mimetic, IRF4 mutants rescued proliferation under IRE1 silencing. Functional studies revealed that IRF4 engages the E2F1 and CDC25A genes and promotes CDK2 activation to drive cell-cycle progression. Our results advance mechanistic understanding of IRE1 and IRF4 in MM.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003096"},"PeriodicalIF":9.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hedgehog-stimulated phosphorylation at multiple sites activates Ci by altering Ci-Ci interfaces without full Suppressor of Fused dissociation.","authors":"Hoyon Kim, Jamie C Little, Jiashen Li, Bryna Patel, Daniel Kalderon","doi":"10.1371/journal.pbio.3003105","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003105","url":null,"abstract":"<p><p>Hedgehog (Hh) proteins elicit dose-dependent transcriptional responses by binding Patched receptors to activate transmembrane Smoothened (Smo) proteins. Activated Smo inhibits Ci/Gli transcription factor phosphorylation by Protein Kinase A and consequent proteolytic processing to repressor forms; it also promotes nuclear transport and activity of full-length Ci/Gli proteins to induce Hh target genes. Smo-activated Fused (Fu) kinase drives Ci activation in Drosophila, while Suppressor of Fused (Su(fu)) counters full-length Ci/Gli activity and stabilizes full-length Ci/Gli by direct binding to at least three surfaces. Here, we used CRISPR-generated designer ci alleles to investigate alterations to Fu phosphorylation sites and to regions around Ci-Su(fu) interfaces under physiological conditions in Drosophila imaginal wing discs. Surprisingly, we identified alterations that activate Ci without significant loss of stabilization by Su(fu) and contributions of multiple Fu target sites to Ci activation in the absence of Su(fu), suggesting that the affected sites mediate Ci activation by regulating Ci-Ci, rather than Ci-Su(fu) interactions. We propose that those interactions maintain full-length Ci in a closed conformation that also facilitates, and is stabilized by, cooperative Ci-Su(fu) binding. Access to binding partners necessary for Ci activation is promoted through phosphorylation of at least four Fu sites on Ci, likely by directly disrupting Ci-Ci contacts and one Ci-Su(fu) interface without substantial Ci-Su(fu) dissociation, contrary to previous proposals. We also found that the Ci binding partner, Costal 2 (Cos2), which silences Ci in the absence of Hh, can facilitate Ci activation by Fu kinase.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003105"},"PeriodicalIF":9.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144003844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Top-down and bottom-up interactions rely on nested brain oscillations to shape rhythmic visual attention sampling.","authors":"Jelena Trajkovic, Domenica Veniero, Simon Hanslmayr, Satu Palva, Gabriela Cruz, Vincenzo Romei, Gregor Thut","doi":"10.1371/journal.pbio.3002688","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002688","url":null,"abstract":"<p><p>Adaptive visual processing is enabled through the dynamic interplay between top-down and bottom-up (feedback/feedforward) information exchange, presumably propagated through brain oscillations. Here, we causally tested for the oscillatory mechanisms governing this interaction in the human visual system. Using concurrent transcranial magnetic stimulation-electroencephalography (TMS-EEG), we emulated top-down signals by a single TMS pulse over the frontal eye field (right FEF), while manipulating the strength of sensory input through the presentation of moving concentric gratings (compared to a control-TMS site). FEF-TMS without sensory input led to a top-down modulated occipital phase realignment, alongside higher fronto-occipital phase connectivity, in the alpha/beta band. Sensory input in the absence of FEF-TMS increased occipital gamma activity. Crucially, testing the interaction between top-down and bottom-up processes (FEF-TMS during sensory input) revealed an increased nesting of the bottom-up gamma activity in the alpha/beta-band cycles. This establishes a causal link between phase-to-power coupling and top-down modulation of feedforward signals, providing novel mechanistic insights into how attention interacts with sensory input at the neural level, shaping rhythmic sampling.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3002688"},"PeriodicalIF":9.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reanalysis of cryo-EM data reveals ALK-cytokine assemblies with both 2:1 and 2:2 stoichiometries.","authors":"Jan Felix, Steven De Munck, J Fernando Bazan, Savvas N Savvides","doi":"10.1371/journal.pbio.3003124","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003124","url":null,"abstract":"<p><p>Activation of Anaplastic lymphoma kinase (ALK) and leukocyte tyrosine kinase (LTK) by their cognate cytokines ALKAL2 and ALKAL1 plays important roles in development, metabolism, and cancer. Recent structural studies revealed ALK/LTK-cytokine assemblies with distinct stoichiometries. Structures of ALK-ALKAL2 and LTK-ALKAL1 complexes with 2:1 stoichiometry determined by X-ray crystallography contrasted the 2:2 ALK-ALKAL2 complexes determined by cryo-EM and X-ray crystallography. Here, we show based on reanalysis of the cryo-EM data deposited in EMPIAR-10930 that over half of the ALK-ALKAL2 particles in the dataset are classified into 2D and 3D classes obeying a 2:1 stoichiometry besides the originally reported structure displaying 2:2 stoichiometry. Unlike particles representing the 2:2 ALK-ALKAL2 complex, particles for the 2:1 ALK-ALKAL2 complex suffer severely from preferred orientations that resulted in cryo-EM maps displaying strong anisotropy. Here, we show that extensive particle orientation rebalancing in cryoSPARC followed by 3D refinement with Blush regularization in RELION constitutes an effective strategy for avoiding map artifacts relating to preferred particle orientations and report a 3D reconstruction of the 2:1 ALK-ALKAL2 complex to 3.2 Å resolution from EMPIAR-10930. This new cryo-EM structure together with the crystal structures of ALK-ALKAL2 and LTK-ALKAL1 complexes with 2:1 stoichiometry reconciles a common receptor dimerization mode for ALK and LTK and provides direct evidence for the presence of an ALK-ALKAL2 complex with 2:1 stoichiometry next to the reported 2:2 stoichiometric assembly in the EMPIAR-10930 dataset. Finally, our analysis emphasizes the importance of public deposition of raw cryo-EM data to allow reanalysis and interpretation.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003124"},"PeriodicalIF":9.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12017499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Purkinje cells of the cerebellum control deceleration of tongue movements.","authors":"Paul Hage, Mohammad Amin Fakharian, Alden M Shoup, Jay S Pi, Ehsan Sedaghat-Nejad, Simon P Orozco, In Kyu Jang, Vivian Looi, Hisham Y Elseweifi, Nazanin Mohammadrezaei, Alexander N Vasserman, Toren Arginteanu, Reza Shadmehr","doi":"10.1371/journal.pbio.3003110","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003110","url":null,"abstract":"<p><p>We use our tongue much like our hands: to interact with objects and transport them. For example, we use our hands to sense properties of objects and transport them in the nearby space, and we use our tongue to sense properties of food morsels and transport them through the oral cavity. But what does the cerebellum contribute to control of tongue movements? Here, we trained head-fixed marmosets to make skillful tongue movements to harvest food from small tubes that were placed at sharp angles to their mouth. We identified the lingual regions of the cerebellar vermis and then measured the contribution of each Purkinje cell (P-cell) to control of the tongue by relying on the brief but complete suppression that they experienced following an input from the inferior olive. When a P-cell was suppressed during protraction, the tongue's trajectory became hypermetric, and when the suppression took place during retraction, the tongue's return to the mouth was slowed. Both effects were amplified when two P-cells were simultaneously suppressed. Moreover, these effects were present even when the pauses were not due to the climbing fiber input. Therefore, suppression of P-cells in the lingual vermis disrupted the forces that would normally decelerate the tongue as it approached the target. Notably, the population simple spike activity peaked near deceleration onset when the movement required precision (aiming for a tube), but not when the movement was for the purpose of grooming. Thus, the P-cells appeared to signal when to stop protrusion as the tongue approached its target.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003110"},"PeriodicalIF":9.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11984719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MSP-tracker: A versatile vesicle tracking software tool used to reveal the spatial control of polarized secretion in Drosophila epithelial cells.","authors":"Jennifer H Richens, Mariia Dmitrieva, Helen L Zenner, Nadine Muschalik, Richard Butler, Jade Glashauser, Carolina Camelo, Stefan Luschnig, Sean Munro, Jens Rittscher, Daniel St Johnston","doi":"10.1371/journal.pbio.3003099","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003099","url":null,"abstract":"<p><p>Understanding how specific secretory cargoes are targeted to distinct domains of the plasma membrane in epithelial cells requires analyzing the trafficking of post-Golgi vesicles to their sites of secretion. We used the RUSH (retention using selective hooks) system to synchronously release an apical cargo, Cadherin 99C (Cad99C), and a basolateral cargo, the ECM protein Nidogen, from the endoplasmic reticulum and followed their movements to the plasma membrane. We also developed an interactive vesicle tracking framework, MSP-tracker and viewer, that exploits developments in computer vision and deep learning to determine vesicle trajectories in a noisy environment without the need for extensive training data. MSP-tracker outperformed other tracking software in detecting and tracking post-Golgi vesicles, revealing that Cad99c vesicles predominantly move apically with a mean speed of 1.1µm/sec. This is reduced to 0.85 µm/sec by a dominant slow dynein mutant, demonstrating that dynein transports Cad99C vesicles to the apical cortex. Furthermore, both the dynein mutant and microtubule depolymerization cause lateral Cad99C secretion. Thus, microtubule organization plays a central role in targeting apical secretion, suggesting that Drosophila does not have distinct apical versus basolateral vesicle fusion machinery. Nidogen vesicles undergo planar-polarized transport to the leading edge of follicle cells as they migrate over the ECM, whereas most Collagen is secreted at trailing edges. The follicle cells therefore bias secretion of different ECM components to opposite sides of the cell, revealing that the secretory pathway is more spatially organized than previously thought.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003099"},"PeriodicalIF":9.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12021295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A nonenzymatic dependency on inositol-requiring enzyme 1 controls cancer cell cycle progression and tumor growth.","authors":"Iratxe Zuazo-Gaztelu, David Lawrence, Ioanna Oikonomidi, Scot Marsters, Ximo Pechuan-Jorge, Catarina J Gaspar, David Kan, Ehud Segal, Kevin Clark, Maureen Beresini, Marie-Gabrielle Braun, Joachim Rudolph, Zora Modrusan, Meena Choi, Wendy Sandoval, Mike Reichelt, David C DeWitt, Pekka Kujala, Suzanne van Dijk, Judith Klumperman, Avi Ashkenazi","doi":"10.1371/journal.pbio.3003086","DOIUrl":"10.1371/journal.pbio.3003086","url":null,"abstract":"<p><p>Endoplasmic-reticulum resident inositol-requiring enzyme 1α (IRE1) supports protein homeostasis via its cytoplasmic kinase-RNase module. Known cancer dependency on IRE1 entails its enzymatic activation of the transcription factor XBP1s and of regulated RNA decay. We discovered surprisingly that some cancer cell lines require IRE1 but not its enzymatic activity. IRE1 knockdown but not enzymatic IRE1 inhibition or XBP1 disruption attenuated cell cycle progression and tumor growth. IRE1 silencing led to activation of TP53 and CDKN1A/p21 in conjunction with increased DNA damage and chromosome instability, while decreasing heterochromatin as well as DNA and histone H3K9me3 methylation. Immunoelectron microscopy detected some endogenous IRE1 protein at the nuclear envelope. Thus, cancer cells co-opt IRE1 either enzymatically or nonenzymatically, which has significant implications for IRE1's biological role and therapeutic targeting.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003086"},"PeriodicalIF":9.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12080931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of NMDA receptor signaling and zinc chelation prevent seizure-like events in a zebrafish model of SLC13A5 epilepsy.","authors":"Deepika Dogra, Van Anh Phan, Sinan Zhang, Cezar Gavrilovici, Nadia DiMarzo, Ankita Narang, Kingsley Ibhazehiebo, Deborah M Kurrasch","doi":"10.1371/journal.pbio.3002499","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002499","url":null,"abstract":"<p><p>SLC13A5 encodes a citrate transporter highly expressed in the brain and is important for regulating intra- and extracellular citrate levels. Mutations in this gene cause rare infantile epilepsy characterized by lifelong seizures, developmental delays, behavioral deficits, poor motor progression, and language impairments. SLC13A5 individuals respond poorly to treatment options; yet drug discovery programs are limited due to a paucity of animal models that phenocopy human symptoms. Here, we used CRISPR/Cas9 to create loss-of-function mutations in slc13a5a and slc13a5b, the zebrafish paralogs to human SLC13A5. slc13a5 mutant larvae showed cognitive dysfunction and sleep disturbances, consistent with SLC13A5 individuals. These mutants also exhibited fewer neurons and a concomitant increase in apoptosis across the optic tectum, a region important for sensory processing. Further, slc13a5 mutants displayed hallmark features of epilepsy, including an imbalance in glutamatergic and GABAergic excitatory-inhibitory gene expression, increased fosab expression, disrupted neurometabolism, and neuronal hyperexcitation as measured in vivo by extracellular field recordings and live calcium imaging. Mechanistically, we tested the involvement of NMDA signaling and zinc chelation in slc13a5 mutant epilepsy-like phenotypes. Slc13a5 protein co-localizes with excitatory NMDA receptors in wild-type zebrafish and NMDA receptor expression is upregulated in the brain of slc13a5 mutant larvae. Additionally, low levels of zinc are found in the plasma membrane of slc13a5 mutants. NMDA receptor suppression and ZnCl2 treatment in slc13a5 mutant larvae rescued neurometabolic and hyperexcitable calcium events, as well as behavioral defects. These data provide empirical evidence in support of the hypothesis that excess extracellular citrate over-chelates the zinc ions needed to regulate NMDA receptor function, leading to sustained channel opening and an exaggerated excitatory response that manifests as seizures. These data show the utility of slc13a5 mutant zebrafish for studying SLC13A5 epilepsy and open new avenues for drug discovery.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3002499"},"PeriodicalIF":9.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12047791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase separation of the PRPP amidotransferase into dynamic condensates promotes de novo purine synthesis in yeast.","authors":"Masak Takaine, Rikuri Morita, Yuto Yoshinari, Takashi Nishimura","doi":"10.1371/journal.pbio.3003111","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003111","url":null,"abstract":"<p><p>De novo purine synthesis (DPS) is up-regulated under conditions of high purine demand to ensure the production of genetic materials and chemical energy, thereby supporting cell proliferation. However, the regulatory mechanisms governing DPS remain unclear. We herein show that PRPP amidotransferase (PPAT), the rate-limiting enzyme in DPS, forms dynamic and motile condensates in Saccharomyces cerevisiae cells under a purine-depleted environment. The formation and maintenance of condensates requires phase separation, which is driven by target of rapamycin complex 1 (TORC1)-induced ribosome biosynthesis. The self-assembly of PPAT molecules facilitates condensate formation, with intracellular PRPP and purine nucleotides both regulating this self-assembly. Moreover, molecular dynamics simulations suggest that clustering-mediated PPAT activation occurs through intermolecular substrate channeling. Cells unable to form PPAT condensates exhibit growth defects, highlighting the physiological importance of condensation. These results indicate that PPAT condensation is an adaptive mechanism that regulates DPS in response to both TORC1 activity and cellular purine demands.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003111"},"PeriodicalIF":9.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12017579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}