Journal of Biological Chemistry最新文献

{"title":"Mechanism-selective inhibition of α-synuclein aggregation by the chaperone-like BRICHOS domain.","authors":"Laurène Adam, Willem Hendrik Molenkamp, Jan Stanislaw Nowak, Azad Farzadfard, Koen Gaarthuis, Rakesh Kumar, Janni Nielsen, Daniel E Otzen, Jan Johansson, Axel Abelein","doi":"10.1016/j.jbc.2026.113117","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113117","url":null,"abstract":"<p><p>Current therapeutic approaches for Parkinson's disease (PD) and other synucleinopathies alleviate symptoms but fail to effectively prevent disease progression. As a result, there is an increasing focus on alternative disease-modifying strategies where molecular chaperones are emerging candidates. Recently, the chaperone-like Bri2 BRICHOS domain has been shown to be a promising therapeutic candidate, inhibiting amyloid formation and associated toxicity of multiple amyloidogenic proteins including human α-synuclein (αSyn). To advance the development of Bri2 BRICHOS as a therapeutic, in vivo tests in mice are necessary, which commonly rely on injections of pre-formed fibrils of mouse αSyn. Here, we investigate the inhibitory mechanism of Bri2 BRICHOS on mouse αSyn aggregation and fibril interaction. In contrast to previous results on human αSyn, we found that Bri2 BRICHOS exhibits a very modest inhibitory effect on mouse αSyn aggregation, which is only observed under gentle shaking or quiescent conditions. While Bri2 BRICHOS binds with similar affinities to the respective fibrils, we observed that differences in the underlying nucleation mechanisms of mouse vs human αSyn fibril formation explain the impaired suppression of mouse αSyn fibrillation under strong shaking conditions. The more fragile nature of mouse αSyn fibrils causes stronger contributions of fibril fragmentation processes compared to surface-catalyzed secondary nucleation - the dominant nucleation mechanism for human αSyn. In conclusion, these findings provide molecular insights into the mechanism-of-action of Bri2 BRICHOS-mediated inhibition of αSyn aggregation as a selective chaperone-based inhibitor of surface-catalyzed secondary nucleation pathways, which facilitates informed choices of in vivo model systems for future treatment studies.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113117"},"PeriodicalIF":4.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Phospho-ubiquitin in Mitochondrial Health and Diseases.","authors":"Kumar Suresh, Christopher Rainvillee, David E Sterner, Matthew S Goldberg, Tauseef R Butt","doi":"10.1016/j.jbc.2026.113128","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113128","url":null,"abstract":"<p><p>Mitochondria play a major role in cellular health, yet their contribution to chronic diseases has been underestimated. Mitochondria are essential for all tissues, and a major source of ATP in high-energy-demand organs such as brain and heart being vulnerable to mitochondrial dysfunction. Failure to repair or remove damaged mitochondria contributes to aging and chronic diseases. Cells have evolved quality control mechanisms, including mitophagy to eliminate damaged mitochondria and mitobiogenesis to replenish them. The ubiquitin-proteasome system (UPS) is responsible for removing misfolded proteins, a process that is highly ATP dependent and therefore reliant on mitochondrial function. In turn, damaged mitochondria are eliminated through coordinated actions of the UPS and lysosomal degradation through mitophagy. Many neurodegenerative diseases are characterized by the presence of disease-specific protein aggregates, such as α-synuclein aggregates in Parkinson's disease and tau neurofibrillary tangles in Alzheimer's disease. These aggregates impair mitochondrial function, while dysfunctional mitochondria generate reactive oxygen species that further exacerbate proteotoxic stress, creating a pathogenic cycle. This highlights the functional interplay between mitochondria and the UPS. Recent studies have uncovered phosphorylation of ubiquitin at Serine 65 by the mitochondrial kinase PINK1 as a key signal of mitochondrial dysfunction. Phospho-Ser65-Ubiquitin (pUb) has emerged as an indicator of mitochondrial health and a potential biomarker for aging and neurodegenerative disease. However, due largely to a lack of tools, little is known about the role of pUb in cellular physiology. Here we review the current landscape of pUb biology, the phospho-ubiquitome, and its role as biomarker for mitochondrial health, and neurodegeneration.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113128"},"PeriodicalIF":4.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel autopolysialylation activity of the ganglioside sialyltransferase ST8Sia5 regulates its secretion and enzyme activity.","authors":"Fumiya Sakamoto, Rina Hatanaka, Masaya Hane, Di Wu, Ken Kitajima, Chihiro Sato","doi":"10.1016/j.jbc.2026.113106","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113106","url":null,"abstract":"<p><p>Polysialic acid (polySia) is a linear polymer of sialic acid, which usually modifies N-glycans on the neural cell adhesion molecule (NCAM) mostly in the brain and is involved in the development of brain. PolySia is also associated with several diseases, including mental disorders and cancers. ST8Sia2 and ST8Sia4 are believed to be the only polysialyltransferases that synthesize polySia on NCAM (NCAM polysialylation). These enzymes are also autopolysialylated. In this study, we first found that ST8Sia5L, a ganglioside-specific sialyltransferase, has an activity to synthesize polysialic acid on ST8Sia5 itself, but does not exhibit the NCAM polysialylation activity. Notably, in silico and biochemical analyses revealed that ST8Sia5L contains a new polysialic acid trapping motif (PSTM) that is essential for polySia elongation, instead of the conventional polysialyltransferase domain (PSTD) found in ST8Sia2 and ST8Sia4. We also found that autopolysialylated ST8Sia5L is secreted from the cells. To identify the autopolysialylation sites involved in secretion, we performed N-glycosylation site disruption experiments, and found that N92 and N277 in the five N-glycosylation sites are important for this phenomenon. Furthermore, the inhibitor experiments showed that certain metalloprotease(s), but not exosomal pathways, are involved in the secretion. Notably, the secreted autopolysialylated enzyme showed no ganglioside-sialylation activity; however, the activity was recovered when polySia was removed by sialidase treatment. Overall, we show that autopolysialylation of ST8Sia5L regulates both its secretion and the conventional sialyltransferase activity.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113106"},"PeriodicalIF":4.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An intricate functional relationship between NuA4 and Sfp1 regulates ribosome biogenesis in response to nutrient availability.","authors":"Ke Xu, Stéphanie Bianco, Charles Joly Beauparlant, Valérie Côté, Lara Herrmann, Arnaud Droit, Michael Downey, Amine Nourani, Jacques Côté","doi":"10.1016/j.jbc.2026.113107","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113107","url":null,"abstract":"<p><p>Ribosome biogenesis is a crucial process requiring enormous transcriptional output. In budding yeast, the expression of 138 ribosomal protein (RP) genes and over 200 ribosome biogenesis (RiBi) genes is regulated by an intricate network of factors, including the nutrient-sensitive transcription activator Sfp1 and the NuA4 coactivator/acetyltransferase complex. Nutrient starvation or inhibition of TORC1 by rapamycin leads to repression of RP and RiBi genes, in part through blocking Sfp1 nuclear localization and NuA4-dependent chromatin acetylation. Here, we demonstrate that Sfp1 physically interacts with NuA4 in a TORC1-dependent manner. Our results indicate that Sfp1, along with NuA4, regulate the transcription of RiBi and RP genes via distinct mechanisms depending on promoter architectures. Sfp1 promotes histone acetylation at the promoters without affecting NuA4 recruitment. In contrast, NuA4 does impact Sfp1 binding but specifically at two classes of RP genes. Importantly, NuA4 acetylates Sfp1 at lysines 655 and 657, regulating its function. Cells expressing Sfp1 with acetyl-mimicking mutations exhibit increased expression of RiBi genes while RP genes remain stable. However, the same mutants lead to the loss of Sfp1 binding/activity at RiBi genes when cells are under non-optimal growth conditions. Mimicking constitutive acetylation of Sfp1 also limits the transcriptional burst of RP genes upon addition of glucose. Altogether, these results draw an intricate functional relationship between Sfp1 and NuA4 to control ribosome biogenesis, fine-tuning transcription output in different growth conditions.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113107"},"PeriodicalIF":4.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruption of GxxxG motifs in pATOM36 impairs biogenesis of the mitochondrial protein translocase of the outer membrane in Trypanosoma brucei.","authors":"Stephan Berger, Siri Speck, André Schneider, Christoph von Ballmoos","doi":"10.1016/j.jbc.2026.113126","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113126","url":null,"abstract":"<p><p>Mitochondrial biogenesis requires efficient import of cytosolically produced proteins and correct segregation of the mitochondrial genome during cytokinesis. In T. brucei, a parasitic protozoan with a single mitochondrion harboring a single-unit mitochondrial genome, protein import across the outer membrane is mediated by the ATOM complex. An important, yet poorly understood role is played by the integral membrane protein pATOM36 of the outer mitochondrial membrane, which is essential for both ATOM complex assembly and mitochondrial DNA segregation. Here, we combined in vivo functional mutational analysis and structural modeling to investigate the function of pATOM36. AlphaFold3-based models predict five highly tilted helices forming a funnel-shaped cavity open toward the cytoplasm, reminiscent of membrane protein insertases. In the model, the protein is sealed towards the mitochondrial intermembrane space by tight helix packing, with conserved GxxxG motifs potentially facilitating these helix-helix interactions. Progressive replacement of these glycines by isoleucines does not affect protein production or correct localization but leads to defective ATOM complex biogenesis and arrest of growth, while mitochondrial DNA segregation is largely unaffected. Based on the predicted structure, these effects can be rationalized by hydrophobic bulking that interferes with associated electrostatic interactions. This hypothesis is supported by experimental mutational analysis of the respective electrostatic interactions in the presence of native GxxxG motifs. Together, our data support the hypothesis that pATOM36 functions as an outer mitochondrial insertase and arose by convergent evolution. The GxxxG motifs, also found in unrelated yeast and human outer membrane insertases, are crucial for protein activity.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113126"},"PeriodicalIF":4.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM25 enhances hypoxia signaling by catalyzing K11-linked polyubiquitination and stabilization of HIF-α.","authors":"Ziyi Li, Jun Li, Zhi Li, Rui Wang, Le Yuan, Yanan Song, Yanyi Wang, Runkun Yan, Fuxiang Lai, Jing Wang, Wuhan Xiao","doi":"10.1016/j.jbc.2026.113125","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113125","url":null,"abstract":"<p><p>TRIM25 is an E3 ubiquitin ligase involved in various cellular processes due to its enzymatic activity. In particular, it plays a role in antiviral innate immunity. Here, we demonstrate that TRIM25 modulates hypoxia signaling. TRIM25 interacts with HIF-1α and HIF-2α, stabilizing them. TRIM25 catalyzes K11-linked polyubiquitination of HIF-1α at K719 and K721 and of HIF-2α at K709. This results in the stabilization of the proteins and enhanced hypoxia signaling. Moreover, TRIM25-mediated augmentation of hypoxia signaling depends on HIF-1α. Trim25-deficient mice are more sensitive to hypoxia, and zebrafish lacking trim25 show a similar phenotype. These data reveal TRIM25's role in regulating hypoxia signaling and provide insight into a new mechanism that modulates the stabilization and activity of HIF-1α and HIF-2α.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113125"},"PeriodicalIF":4.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of salt concentration and free magnesium on human beta-cardiac myosin reveal important details about the conserved mechanochemical mechanism.","authors":"Jinghua Ge, Michael R Ebert, Skylar M L Bodt, Satyabrata Majumder, Wen Ma, Christopher M Yengo","doi":"10.1016/j.jbc.2026.113114","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113114","url":null,"abstract":"<p><p>The myosin ATPase cycle is dramatically accelerated by the presence of actin, while the structural details of actin-activation are still unclear. We found that a dilated cardiomyopathy mutation, E525K, in human beta-cardiac myosin subfragment 1 (S1) enhanced actin-activation of phosphate release and lever arm rotation ∼3-fold. We hypothesized that abolishment of the conserved 484-525 salt bridge allows for the lysine at residue 525 to more readily interact with actin. Indeed, we found that actin-activated ATPase activity of E525K was quite resistant to changes in salt concentration (20 mM to 100 mM KCl) compared to the wild-type (WT) motor, while in vitro actin-gliding velocities were similarly altered. Direct measurements of pyrene actin binding revealed that the E525K mutation accelerates attachment to actin. We found that the actin-activated ATPase activity of E525K was less sensitive to magnesium (Mg) than WT indicating that the mutation allosterically alters the coordination of Mg in the active site. In addition, the Mg dependence of ADP release was significantly faster in the mutant at low Mg. Molecular dynamics simulations demonstrate that E525K increases the conformational variation of the active site in the ADP-bound state. Our results suggest that the E525K mutation enhances actin affinity by accelerating the transition from weak to strong actin binding, which highlights the importance of the activation loop/relay helix communication pathway during actin-activated Pi-release. In addition, E525K alters Mg coordination in the active site further demonstrating the importance of the 484-525 salt bridge in allosterically coupling the active site and actin binding region.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113114"},"PeriodicalIF":4.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comprehensive Discovery Platform for ELOVL1 Small Molecule Inhibitors Targeting Very Long Chain Fatty Acid Synthesis in Adrenoleukodystrophy.","authors":"Stephanie Holley, Gary Asmussen, Becky Lam, Zhonglin Zhao, Brian Freed, Lilu Guo, Zuzana Dostalova, Buyun Tang, Michael Kothe, Paul Lang, Donghui Wang, Martin Hanus, Alexei Belenky, Mandy Cromwell, Alla Kloss, Tatiana Gladysheva","doi":"10.1016/j.jbc.2026.113103","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113103","url":null,"abstract":"<p><p>Adrenoleukodystrophy (ALD or X-ALD) is a rare devastating neurological disease caused by mutations in the ATP binding cassette D1 (ABCD1) gene, product of which is involved in the transport of Very Long Chain Fatty Acids (VLCFAs) into peroxisome for degradation by β-oxidation. Deficiency in ABCD1 results in VLCFAs accumulation in many tissues, including the brain and spinal cord. Elevated VLCFA levels, specifically C26:0, are consistent biochemical markers of ALD and are implicated in the ALD pathogenesis. ALD disease is manifested by multiple phenotypes: the most severe cerebral disease (cerebral ALD, cALD), adrenomyeloneuropathy (AMN) and adrenal insufficiency (Addison disease). VLCFA's accumulation is a hallmark of all ALD phenotypes, and reduction/normalization of VLCFA's level is an attractive approach for the treatment of all ALD manifestations. VLCFAs synthesis involves enzymes from Elongase of Very Long chain fatty acids (ELOVL) enzyme family with ELOVL1 being a rate-limiting enzyme in C26:0 synthesis, making ELOVL1 an attractive target for medical intervention in ALD via Substrate Reduction Therapy (SRT). In this paper, we describe the in vitro assays established in support of medicinal chemistry efforts to develop small molecule ELOVL1 inhibitors for ALD. Notably, we developed novel breakthrough in vitro methods to monitor enzymatic and cellular ELOVL1 activity that enabled high-throughput screening (HTS) of Sanofi library collections. We successfully identified CNS active small molecule ELOVL1 inhibitors shown to be efficacious in reduction of C26:0 VLCFA levels in cells and multiple tissues including brain and spinal cord in animal models.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113103"},"PeriodicalIF":4.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of ligand recognition by choline-O-acetyltransferase reveals thiol-reactive assay interference and weak ligand affinity in solution.","authors":"Nina Forsgren, Frida Jonsson, Marcus Carlsson, Robin Afshin Sander, Andreas Larsson, Pernilla Lindén, Anna Linusson, Cecilia Springer Engdahl, Daniel Wiktelius, Fredrik Ekström","doi":"10.1016/j.jbc.2026.113115","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113115","url":null,"abstract":"<p><p>Choline O-acetyltransferase (ChAT) catalyzes the biosynthesis of acetylcholine and is a cysteine-rich enzyme that has been investigated using a range of biochemical and structural approaches. Existing ChAT ligands rely on electrophilic or unstable scaffolds that limit their suitability for biological systems. Prior work established that arylvinylpyridiniums (AVPs) are substrate mimics that undergo ChAT-catalyzed hydrothiolation with CoA to form covalent AVP-CoA adducts. Here, we applied a structure-guided strategy to design non-reactive ligands intended to mimic key features of the AVP-CoA binding pose while avoiding covalent reactivity. Nineteen analogs were synthesized and evaluated across complementary biochemical, structural, and biophysical assays. X-ray crystallography confirmed that the new ligands bind within the ChAT tunnel similar to AVP-CoAs. Importantly, the high cysteine content of ChAT, especially within a reactive CXCXXC motif, rendered the enzyme susceptible to modification by the widely used 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin (CPM) reagent used for measuring ChAT activity, leading to confounding results in thiol-dependent activity assays. Enzyme-free counter-screens demonstrated that all apparent inhibitory activity arose from interference with assay readout rather than true enzymatic inhibition. Surface plasmon resonance measurements established that none of the designed ligands display detectable reversible affinity for ChAT, despite their crystallographically validated poses, and no selectivity over the related enzyme carnitine-O-acetyltransferase (CrAT) was observed. These findings demonstrate that confirmed binding with X-ray crystallography is insufficient to confer functional interaction with ChAT and highlight the susceptibility of this enzyme to thiol-reactive assay artefacts. More broadly, this work underscores the necessity of integrating orthogonal biophysical validation when studying ligand binding to cysteine-rich enzymes.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113115"},"PeriodicalIF":4.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of chromatin dynamics by a calcium-dependent nucleoskeleton.","authors":"María José González, Michele Angela Rodrigues, Santo Diprima, Dejian Zhao, Thais Fernandes Bassani, Clara Couto Fernandez, Emma Kruglov, Michael H Nathanson, Dawidson Assis Gomes","doi":"10.1016/j.jbc.2026.113104","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113104","url":null,"abstract":"<p><p>Growth factors selectively activate calcium signaling pathways in the cell nucleus, which in turn regulate gene transcription and other intranuclear events, but the specific way this is accomplished is not entirely understood. Growth factors increase inositol 1,4,5-trisphosphate (IP3) in the nucleus, which in turn releases calcium from intranuclear IP3 receptors (ITPRs), and the present study shows that this leads to transient assembly of an actin nucleoskeleton that associates with intranuclear non-muscle myosin 2A (MYH9). Mass spectrometry suggests that much of the MYH9 cargo consists of components of the gene transcription machinery, and chromatin immunoprecipitation identified a number of specific genes that associate with the myosin in response to stimulation with growth factors. Together, these findings suggest that growth factors initiate gene transcription by transiently assembling an actin nucleoskeleton that works with MYH9 to bring specific genes to the transcription machinery.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113104"},"PeriodicalIF":4.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}