Kaushik Amancherla, Angela M Taravella Oill, Xavier Bledsoe, Arianna L Williams, Nelson Chow, Shilin Zhao, Quanhu Sheng, David W Bearl, Robert D Hoffman, Jonathan N Menachem, Hasan K Siddiqi, Douglas M Brinkley, Evan D Mee, Niran Hadad, Vineet Agrawal, Jeffrey Schmeckpepper, Aniket S Rali, Stacy Tsai, Eric H Farber-Eger, Quinn S Wells, Jane E Freedman, Nathan R Tucker, Kelly H Schlendorf, Eric R Gamazon, Ravi V Shah, Nicholas Banovich
{"title":"Dynamic responses to rejection in the transplanted human heart revealed through spatial transcriptomics.","authors":"Kaushik Amancherla, Angela M Taravella Oill, Xavier Bledsoe, Arianna L Williams, Nelson Chow, Shilin Zhao, Quanhu Sheng, David W Bearl, Robert D Hoffman, Jonathan N Menachem, Hasan K Siddiqi, Douglas M Brinkley, Evan D Mee, Niran Hadad, Vineet Agrawal, Jeffrey Schmeckpepper, Aniket S Rali, Stacy Tsai, Eric H Farber-Eger, Quinn S Wells, Jane E Freedman, Nathan R Tucker, Kelly H Schlendorf, Eric R Gamazon, Ravi V Shah, Nicholas Banovich","doi":"10.1101/2025.02.28.640852","DOIUrl":"https://doi.org/10.1101/2025.02.28.640852","url":null,"abstract":"<p><p>Allograft rejection following solid-organ transplantation is a major cause of graft dysfunction and mortality. Current approaches to diagnosis rely on histology, which exhibits wide diagnostic variability and lacks access to molecular phenotypes that may stratify therapeutic response. Here, we leverage image-based spatial transcriptomics at sub-cellular resolution in longitudinal human cardiac biopsies to characterize transcriptional heterogeneity in 62 adult and pediatric heart transplant (HT) recipients during and following histologically-diagnosed rejection. Across 28 cell types, we identified significant differences in abundance in <i>CD4</i> + and <i>CD8</i> + T cells, fibroblasts, and endothelial cells across different biological classes of rejection (cellular, mixed, antibody-mediated). We observed a broad overlap in cellular transcriptional states across histologic rejection severity and biological class and significant heterogeneity within rejection severity grades that would qualify for immunomodulatory treatment. Individuals who had resolved rejection after therapy had a distinct transcriptomic profile relative to those with persistent rejection, including 216 genes across 6 cell types along pathways of inflammation, IL6-JAK-STAT3 signaling, IFNα/IFNγ response, and TNFα signaling. Spatial transcriptomics also identified genes linked to long-term prognostic outcomes post-HT. These results underscore importance of subtyping immunologic states during rejection to stratify immune-cardiac interactions following HT that are therapeutically relevant to short- and long-term rejection-related outcomes.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M P Forrest, N H Piguel, V A Bagchi, L E Dionisio, S Yoon, M Dos Santos, M S LeDoux, P Penzes
{"title":"Impairment of homeostatic structural plasticity caused by the autism and schizophrenia-associated 16p11.2 duplication.","authors":"M P Forrest, N H Piguel, V A Bagchi, L E Dionisio, S Yoon, M Dos Santos, M S LeDoux, P Penzes","doi":"10.1101/2025.03.06.641931","DOIUrl":"https://doi.org/10.1101/2025.03.06.641931","url":null,"abstract":"<p><p>Homeostatic plasticity is essential for information processing and the stability of neuronal circuits, however its relevance to neuropsychiatric disorders remains unclear. The 16p11.2 duplication (BP4-BP5) is a genetic risk factor that strongly predisposes to a range of severe mental illnesses including autism, schizophrenia, intellectual disability, and epilepsy. The duplication consists of a 600 kb region on chromosome 16, including 27 protein-coding genes, with poorly defined effects on neuronal structure and function. Here, we used a mouse model of the 16p11.2 duplication to investigate the impact of this variant on synaptic structure and downstream homeostatic plasticity. We find that 16p11.2 duplication neurons exhibit overly branched dendritic arbors and excessive spine numbers, which host an overabundance of surface AMPA receptor subunit GluA1. Using a homeostatic plasticity paradigm, we show that 16p11.2 duplication neurons fail to undergo synaptic upscaling upon activity deprivation, consistent with disrupted structural plasticity. We also observe that the increased surface abundance of GluA1 occludes further insertion events, a critical mechanism for synaptic plasticity. Finally, we show that genetically correcting the dosage of 16p11.2-encoded <i>Prrt2</i> to wild-type levels rescues structural spine phenotypes. Our work suggests that aberrant plasticity could contribute to the etiology of neuropsychiatric disorders.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mi-Kyung Yun, Chitra Subramanian, Karen Miller, Pamela Jackson, Christopher D Radka, Charles O Rock
{"title":"Isoleucine binding and regulation of <i>Escherichia coli</i> and <i>Staphylococcus aureus</i> threonine dehydratase (IlvA).","authors":"Mi-Kyung Yun, Chitra Subramanian, Karen Miller, Pamela Jackson, Christopher D Radka, Charles O Rock","doi":"10.1101/2025.03.06.641827","DOIUrl":"https://doi.org/10.1101/2025.03.06.641827","url":null,"abstract":"<p><p>Threonine deaminase (IlvA) is the first enzyme in the isoleucine branch of the branched-chain amino acid biosynthetic pathway. Kinetic studies of isoleucine feedback inhibition of Escherichia coli IlvA (EcIlvA) introduced the concept of allosteric regulation in enzymes. While the crystal structure of EcIlvA shows a tetrameric assembly of protomers with distinct catalytic and regulatory domains, the isoleucine binding site within the regulatory domain (EcIlvA_R) and its regulatory mechanism remained undefined. Here, we present the high-resolution crystal structure of the EcIlvA_R•Ile complex, identifying the isoleucine binding site. The EcIlvA_R•Ile complex reveals that isoleucine binding induces a conformational change in Phe352, propagating a 23 Å shift down the regulatory domain. We propose this conformational shift forms an allosteric pathway that extends to the adjacent protomer's active site, mediating allosteric regulation across the protomer-protomer interface. Supporting this, the EcIlvA(F352A) mutant, though binding isoleucine with high affinity, is not inhibited due to the absence of the Phe352 sidechain. Additionally, Staphylococcus aureus IlvA (SaIlvA) is not feedback-regulated by isoleucine. Structural analysis of the SaIlvA regulatory domain reveals a different subdomain organization, preventing isoleucine binding. These findings enhance our understanding of IlvA's allosteric regulation and offer opportunities for engineering feedback-resistant IlvA variants for biotechnological applications.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Simona Dalin, Sophie Webster, Neal Sugawara, Qiuqin Wu, Shu Zhang, Carmen Macias, Elena Sapède, Tracy Cui, Victoria Liang, Laura Tran, Rameen Beroukhim, James E Haber
{"title":"Mutations and structural variants arising during double-strand break repair.","authors":"Simona Dalin, Sophie Webster, Neal Sugawara, Qiuqin Wu, Shu Zhang, Carmen Macias, Elena Sapède, Tracy Cui, Victoria Liang, Laura Tran, Rameen Beroukhim, James E Haber","doi":"10.1101/2025.02.28.640809","DOIUrl":"10.1101/2025.02.28.640809","url":null,"abstract":"<p><p>Double-strand break (DSB) repair is highly mutagenic compared to normal replication. In budding yeast, repair of an HO endonuclease-induced DSB at <i>MATα</i> can be repaired by using a transcriptionally silent <i>HMR::Kl-URA3</i> donor. During repair, -1 deletions in homonucleotide runs are strongly favored over +1 insertions, whereas during replication, spontaneous +1 and -1 events are equal. Microhomology-bounded, repair-associated intragenic deletions (IDs) are recovered 12 times more frequently than tandem duplications (TDs). IDs have a mean length of 56 bp, while TDs average 22 bp. These data suggest a picture of the structure of the repair replication fork: IDs and TDs occur within the open structure of a migrating D-loop, where the 3' end of a partly copied new DNA strand can dissociate and anneal with a single-stranded region of microhomology that lies either ~80 bp ahead or ~40 bp behind the 3' end. Another major class of repair-associated mutations (~10%) are interchromosomal template switches (ICTS), even though the <i>K. lactis URA3</i> sequence in <i>HMR</i> is only 72% identical (homeologous) with <i>S. cerevisiae ura3-52</i>. ICTS events begin and end at regions of short (~7 bp) microhomology; however, ICTS events are constrained to the middle of the copied sequence. Whereas microhomology usage in intragenic deletions is not influenced by adjacent homeology, we show that extensive pairing of adjacent homeology plays a critical role in ICTS. Thus, although by convention, structural variants are characterized by the precise base pairs at their junction, microhomology-mediated template switching actually requires alignment of extensive adjacent homeology.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexandra M Kaloss, Caroline de Jager, Kennedie Lyles, Nathalie A Groot, Jackie Zhu, Yu Lin, Hehuang Xie, John B Matson, Michelle H Theus
{"title":"Tie2-Dependent Mechanisms Promote Leptomeningeal Collateral Remodeling and Reperfusion Following Stroke.","authors":"Alexandra M Kaloss, Caroline de Jager, Kennedie Lyles, Nathalie A Groot, Jackie Zhu, Yu Lin, Hehuang Xie, John B Matson, Michelle H Theus","doi":"10.1101/2025.02.28.640890","DOIUrl":"https://doi.org/10.1101/2025.02.28.640890","url":null,"abstract":"<p><p>Leptomeningeal collaterals are distal pial arterial anastomotic vessels that provide an alternative route for redistributing cerebral blood flow following arterial obstruction, thereby limiting tissue damage. However, the regulatory mechanisms and strategies to enhance this adaptive response remain under investigation. This study explored the pharmacological effects of Tie2 receptor activation, using the peptide agonist Vasculotide, following permanent middle cerebral artery occlusion (pMCAO). Vasculotide improved collateral growth and remodeling, which correlated with reduced infarct volume, enhanced blood flow, and functional recovery within 24hrs post-pMCAO. In contrast, collateral growth was attenuated in Tie2 and EphA4/Tie2 double knockdown mice, while the loss of EphA4 increased Tie2 and Ang-1 expression and mimicked the positive effects of Vasculotide following stroke. Furthermore, bulk RNA sequencing of meningeal tissue identified key transcriptomic changes, including alterations in AJ-associated transcripts, such as <i>Krt5</i> , <i>Krt14</i> , and <i>Col17a1</i> , in the ipsilateral meninges of both endothelial cell-specific EphA4 knockout and Vasculotide-treated mice. Krt5 expression was found upregulated on meningeal arterial vascular network in injured KO mice, highlighting a potential new mediator of meningeal vascular remodeling. These findings illustrate that EphA4 and Tie2 play opposing roles in collateral remodeling, including the regulation of Krt5. Modulating their activity could potentially enhance the collateral response to stroke.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rui Tang, Aixiang Ding, Chen Fu, Kentaro Umerori, Marvin Rivera, Daniel S Alt, Christopher M Carmean, Li Li, Steven J Eppell, Anthony Wynshaw-Boris, Eben Alsberg
{"title":"Three-dimensional tissue platform co-laid with native collagen fibers and cells for phenotypic screening of stem cell interactions.","authors":"Rui Tang, Aixiang Ding, Chen Fu, Kentaro Umerori, Marvin Rivera, Daniel S Alt, Christopher M Carmean, Li Li, Steven J Eppell, Anthony Wynshaw-Boris, Eben Alsberg","doi":"10.1101/2025.02.28.640824","DOIUrl":"https://doi.org/10.1101/2025.02.28.640824","url":null,"abstract":"<p><p>Phenotypic screening of cell-cell and cell-matrix interactions is critical yet challenging for drug discovery and disease modeling. In this study, a scalable 3D tissue platform was developed by co-laying extracted natural insoluble collagen fibers, mesenchymal stem cells, endothelial cells, and neural progenitor cells for phenotypic screening. Cell growth and interactions were enhanced in the co-laid platform, evident through increased cell proliferation, viability, and vascularization. Dense vascular networks rapidly formed through cell-cell and cell-matrix interactions without adding a traditionally needed growth factor set. Both <i>in vitro</i> and implantation studies confirmed that these blood vessels were of human origin. To evaluate the phenotypic screening of cell-cell and cell-matrix interactions, we propose a phenotype screening prototype for stem cell interactions that utilized multivariate analysis encompassing both cell-cell and cell-matrix interactions and demonstrated its effectiveness to screen vasculature formation and autism spectrum disorder (ASD) models. Using the prototype, we confirmed that collagen crosslinking, ROCK, WNT, and YAP pathways impact vasculogenesis. In addition, ASD donor-derived neural progenitor cells can be distinguished from non-ASD control donor-derived neural progenitor cells.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Katherine A Maniates, Saai Suryanarayanan, Alissa Rumin, Morgan Lewin, Andrew Singson, Ann M Wehman
{"title":"Sperm activation for fertilization requires robust activity of the TAT-5 lipid flippase.","authors":"Katherine A Maniates, Saai Suryanarayanan, Alissa Rumin, Morgan Lewin, Andrew Singson, Ann M Wehman","doi":"10.1101/2025.03.06.641851","DOIUrl":"https://doi.org/10.1101/2025.03.06.641851","url":null,"abstract":"<p><p>During fertilization, sperm and egg membranes signal and fuse to form a zygote and begin embryonic development. Here, we investigated the role of lipid asymmetry in gametogenesis, fertilization, and embryogenesis. We find that phosphatidylethanolamine asymmetry is lost during meiosis prior to phosphatidylserine exposure. We show that TAT-5, the P4-ATPase that maintains phosphatidylethanolamine asymmetry, is required for both oocyte formation and sperm activation, albeit at different levels of flippase activity. Loss of TAT-5 significantly decreases fertility in both males and hermaphrodites and decreases sperm activation. TAT-5 localizes to the plasma membrane of primary spermatocytes but is sorted away from maturing spermatids during meiosis. Our findings demonstrate that phosphatidylethanolamine asymmetry plays key roles during gametogenesis and sperm activation, expanding the roles of lipid dynamics in developmental cell fusion.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zachary M Koh, Ricky Avalos Arceo, Jacob Hammer, Khang Chau, Sarah E W Light, Antonio Dolojan, Michał Januszewski, Fabian Svara, Cody J Smith
{"title":"An ultrastructural map of a spinal sensorimotor circuit reveals the potential of astroglial modulation.","authors":"Zachary M Koh, Ricky Avalos Arceo, Jacob Hammer, Khang Chau, Sarah E W Light, Antonio Dolojan, Michał Januszewski, Fabian Svara, Cody J Smith","doi":"10.1101/2025.03.05.641432","DOIUrl":"10.1101/2025.03.05.641432","url":null,"abstract":"<p><p>Information flow through circuits is dictated by the precise connectivity of neurons and glia. While a single astrocyte can contact many synapses, how glial-synaptic interactions are arranged within a single circuit to impact information flow remains understudied. Here, we use the local spinal sensorimotor circuit in zebrafish as a model to understand how neurons and astroglia are connected in a vertebrate circuit. With semi-automated cellular reconstructions and automated approaches to map all the synaptic connections, we identified the precise synaptic connections of the local sensorimotor circuit, from dorsal root ganglia neurons to spinal interneurons and finally to motor neurons. This revealed a complex network of interneurons that interact in the local sensorimotor circuit. We then mapped the glial processes within tripartite synapses in the circuit. We demonstrate that tripartite synapses are equally distributed across the circuit, supporting the idea that glia can modulate information flow through the circuit at different levels. We show that multiple astroglia, including bona fide astrocytes, contact synapses within a single sensory neuron's circuit and that each of these astroglia can contact multiple parts of the circuit. This detailed map reveals an extensive network of connected neurons and astroglia that process sensory stimuli in a vertebrate. We then utilized this ultrastructural map to model how synaptic thresholding and glial modulation could alter information flow in circuits. We validated this circuit map with GCaMP6s imaging of dorsal root ganglia, spinal neurons and astroglia. This work provides a foundational resource detailing the ultrastructural organization of neurons and glia in a vertebrate circuit, offering insights in how glia could influence information flow in complex neural networks.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Iqbal Ahmad, Jing Zhang, Rongrong Li, Wenqiang Su, Weiqi Liu, You Wu, Ilyas Khan, Xiaomeng Liu, Lian-Feng Li, Sunan Li, Yong-Hui Zheng
{"title":"Murine Leukemia Virus GlycoGag Antagonizes SERINC5 via ER-phagy Receptor RETREG1.","authors":"Iqbal Ahmad, Jing Zhang, Rongrong Li, Wenqiang Su, Weiqi Liu, You Wu, Ilyas Khan, Xiaomeng Liu, Lian-Feng Li, Sunan Li, Yong-Hui Zheng","doi":"10.1101/2025.03.06.641798","DOIUrl":"10.1101/2025.03.06.641798","url":null,"abstract":"<p><p>Serine incorporator 5 (SERINC5) is a host restriction factor that targets certain enveloped viruses, including human immunodeficiency virus type 1 (HIV-1) and murine leukemia virus (MLV). It integrates into the viral envelope from the cell surface, inhibiting viral entry. SERINC5 is transported to the cell surface via polyubiquitination, while a single K130R mutation retains it in the cytoplasm. Both HIV-1 Nef and MLV glycoGag proteins antagonize SERINC5 by reducing its expression in producer cells. Here, we report that MLV glycoGag employs selective autophagy to downregulate SERINC5, demonstrating a more potent mechanism for decreasing its cell surface expression. Although glycoGag is a type II integral membrane protein, it primarily localizes to the cytoplasm and undergoes rapid proteasomal degradation. Employing the K130R mutant, we show that Nef, primarily associated with the plasma membrane, downregulates SERINC5 only after it has trafficked to the cell surface, whereas glycoGag can reduce its expression before reaching the plasma membrane while still in the cytoplasm. Nonetheless, an interaction with SERINC5 stabilizes and recruits glycoGag to the plasma membrane, enabling it to downregulate SERINC5 from the cell surface. Through affinity-purified mass spectrometry analysis combined with CRISPR/Cas9 knockouts, we find that glycoGag's activity depends on reticulophagy regulator 1 (RETREG1), an ER-phagy receptor. Further knockout experiments of critical autophagy genes demonstrate that glycoGag downregulates cytoplasmic SERINC5 via micro-ER-phagy. These findings provide crucial new insights into the ongoing arms race between retroviruses and SERINC5 during infection.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alina Emelianova, Pablo L Garcia, Daniel Tan, Jerelle A Joseph
{"title":"Prediction of small-molecule partitioning into biomolecular condensates from simulation.","authors":"Alina Emelianova, Pablo L Garcia, Daniel Tan, Jerelle A Joseph","doi":"10.1101/2025.03.04.641530","DOIUrl":"10.1101/2025.03.04.641530","url":null,"abstract":"<p><p>Predicting small-molecule partitioning into biomolecular condensates is key to developing drugs that selectively target aberrant condensates. However, the molecular mechanisms underlying small-molecule partitioning remain largely unknown. Here, we first exploit atomistic molecular dynamics simulations of model condensates to elucidate physicochemical rules governing small-molecule partitioning. We find that while hydrophobicity is a major determinant, solubility becomes a stronger regulator of partitioning in more polar condensates. Additionally, more polar condensates exhibit selectivity toward certain compounds, suggesting that condensate-specific therapeutics can be engineered. Building on these insights, we develop minimal models (MAPPS) for efficient prediction of small-molecule partitioning into biologically relevant condensates. We demonstrate that this approach reproduces atomistic partition coefficients in both model systems and condensates composed of the low complexity domain (LCD) of FUS. Applying MAPPS to various LCD-based condensates shows that protein sequence can exert a selective pressure, thereby influencing small-molecule partitioning. Collectively, our findings reveal that partitioning is driven by both small-molecule-protein affinity and the complex interplay between the compounds and the condensate chemical environment.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}