The FASEB Journal最新文献

{"title":"KCNH6 Potassium Channel Regulates Assembling of Mitochondrial Complex I and Promotes Insulin Secretion in Islet Beta Cells","authors":"Xue-Chun Han,&nbsp;Chang Liu,&nbsp;Ze-Ju Jiang,&nbsp;Zi-Lu Wang,&nbsp;Qi Li,&nbsp;Ying-Chao Yuan,&nbsp;Hao Wang,&nbsp;Jin-Kui Yang","doi":"10.1096/fj.202500707RR","DOIUrl":"https://doi.org/10.1096/fj.202500707RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Mitochondrial glucose metabolism is critical for glucose-stimulated insulin secretion and glucose homeostasis in pancreatic β cells. We previously showed that KCNH6, a voltage-dependent potassium (Kv) channel, participated regulation of insulin secretion in pancreatic β cells, however, its role in mitochondrial metabolism remains unclear. Since we recently found that KCNH6 distributed in mitochondria, in this study, we investigated the role of KCNH6 in regulating mitochondrial function in pancreatic β cells by using a β cell-specific knockout (KCNH6-βKO) mouse model. Proteomics analysis of islets indicated that multiple proteins involved in mitochondrial metabolism were dysregulated in islets of KCNH6-βKO mice. Additionally, KCNH6-deficient β cells exhibited damaged mitochondria morphology and oxidative respiration dysfunction, which manifested as decreased glucose-induced ATP production, elevated NADH/NAD⁺ ratio and ROS levels. Impaired mitochondrial metabolism in βKO islets were significantly alleviated after the re-expression of KCNH6. Mechanistically, a physical interaction between KCNH6 and complex I assembly subunit Ndufa13 was detected, providing direct evidence of KCNH6's ability to regulate mitochondrial function. These results suggested that KCNH6 could be a promising therapeutic target for improving energy metabolism in β cells.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 12","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367326","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":"Distinct cAMP Regulation in Scleroderma Lung and Skin Myofibroblasts Governs Their Dedifferentiation via p38α Inhibition","authors":"Jared D. Baas,&nbsp;John Varga,&nbsp;Carol Feghali-Bostwick,&nbsp;Marc Peters-Golden,&nbsp;Sean M. Fortier","doi":"10.1096/fj.202500694RR","DOIUrl":"https://doi.org/10.1096/fj.202500694RR","url":null,"abstract":"<p>Fibrosis in systemic sclerosis/scleroderma (SSc) is characterized by the progressive accumulation and persistence in multiple organs of pathologic fibroblasts whose contractile properties and exuberant secretion of collagens promote tissue stiffness and scarring. Identifying a tractable mechanism for inactivating and possibly clearing these ultimate effector cells of progressive fibrosis, conventionally termed myofibroblasts (MFs), represents an appealing therapeutic strategy for patients with SSc. This can be accomplished by their phenotypic dedifferentiation, a process known to be promoted by the generation of the intracellular second messenger cyclic AMP (cAMP). Notably, however, the abilities of SSc fibroblasts derived from different tissues to generate cAMP—and dedifferentiate in response to it—have never been directly characterized or compared. Here we compared these two processes in lung and skin MFs derived from patients with SSc. While directly increasing intracellular cAMP induced comparable dedifferentiation of lung and skin SSc MFs, dedifferentiation in response to the well-recognized cAMP stimulus prostaglandin E₂ (PGE₂) was diminished or absent in MFs from skin as compared to lung, in part due to differences in the expression of its target G protein-coupled receptors (GPCRs). Importantly, treatment with a phosphodiesterase 4 inhibitor rescued the dedifferentiating effects of PGE₂ in skin SSc MFs. Finally, both cAMP-mediated and direct pharmacologic inhibition of the MAPK p38α promoted dedifferentiation of lung and skin SSc MFs. We conclude that activation of the cAMP pathway and its subsequent inhibition of p38α dedifferentiates SSc MFs from both lung and skin, and may thus represent a therapeutic strategy to alleviate multi-organ fibrosis in SSc.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 12","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500694RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis as an Emerging Target in Diabetic Osteoporosis","authors":"Chenchen Li,&nbsp;He Gong,&nbsp;Yingying Zhang,&nbsp;Peipei Shi,&nbsp;Shuyu Liu,&nbsp;Qi Zhang","doi":"10.1096/fj.202500415R","DOIUrl":"https://doi.org/10.1096/fj.202500415R","url":null,"abstract":"<div>\u0000 \u0000 <p>Diabetic osteoporosis (DOP), as a metabolic bone disease, leads to an increased risk of fracture in patients and imposes a huge burden on society and individuals. The microenvironment of type two diabetes mellitus (T2DM) may contribute to osteoporosis by triggering cell death in bone tissue. Ferroptosis is a novel type of regulated cell death driven by iron-dependent lipid peroxidation discovered in recent years, and the main molecular mechanism involves dysregulation of iron homeostasis, mitochondrial dysfunction, impaired antioxidant capacity, and accumulation of lipid peroxides. In recent years, there has been increasing evidence that ferroptosis is involved in the pathophysiologic process of DOP. However, its exact role and potential molecular mechanisms have not been fully elucidated. In this paper, the role of ferroptosis in developing T2DM and osteoporosis is reviewed, with the intention of providing novel insights into the pathophysiologic investigation of DOP. Furthermore, possible therapeutic compounds that target the ferroptosis signaling system are presented, and ways for leveraging ferroptosis in the prevention and treatment of DOP are examined. These findings are anticipated to offer new directions for the therapeutic intervention and drug development for DOP.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 12","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500415R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline Disruption of Retinal Pigment Epithelium-Expressed Zebrafish rlbp1b−/− Results in Selective Dim Light Visual Behavior Deficits and Provides a Screening Platform for Evaluating the Pathogenicity of Human RLBP1 Variants","authors":"John D. Fehilly,&nbsp;Tess McCann,&nbsp;Grace Ruddin,&nbsp;Joanna J. Kaylor,&nbsp;Hannah Grenville,&nbsp;Rebecca Ward,&nbsp;Kieran Wynne,&nbsp;Alicia Gómez Sánchez,&nbsp;Elin Strachan,&nbsp;Gabriel H. Travis,&nbsp;Ross F. Collery,&nbsp;Breandán N. Kennedy","doi":"10.1096/fj.202500600R","DOIUrl":"https://doi.org/10.1096/fj.202500600R","url":null,"abstract":"<p>Cellular retinaldehyde binding protein (CRALBP) plays a crucial role in the visual cycle by chaperoning 11-<i>cis</i>-retinoids. Mutations in its encoding gene <i>RLBP1</i> lead to inherited retinal diseases with the common feature of poor night vision. Zebrafish possess two <i>RLBP1</i> paralogs, <i>rlbp1a</i> and <i>rlbp1b,</i> with distinct retinal expression profiles, providing a bespoke opportunity to dissect cell-specific functions of CRALBP. Here, we first resolved conflicting reports on paralog expression by interrogating zebrafish single-cell RNA-sequencing datasets, which revealed predominant <i>rlbp1a</i> expression in Müller glia and <i>rlbp1b</i> expression in the RPE. Using CRISPR-generated zebrafish knockouts, we demonstrated that loss of RPE-expressed <i>rlbp1b</i> selectively impaired optokinetic responses (OKR) with a ~50% reduction in saccade frequency relative to wildtype. This impaired OKR response is only seen when under dim light conditions with no defect seen in standard or bright light rearing conditions. This recapitulates the night blindness presentation in patients with <i>RLBP1</i> mutations. Retinoid profiling of <i>rlbp1b</i> knockout larvae showed significant decreases in 11-<i>cis</i>-retinal (62% reduced) and all-<i>trans</i>-retinal (69% reduced) levels. To explore mechanistic changes following <i>rlbp1b</i> loss, unbiased proteomic profiling was carried out on <i>rlbp1b</i> knockout adult zebrafish eyes. This confirmed the knockout of Cralbpb and revealed significant disruption of proteins involved in vitamin A metabolism, lipid metabolism/storage and ferroptosis. To explore the utility of zebrafish for in vivo pathogenicity assessment of <i>RLBP1</i>, we established a complementation assay using transgenic zebrafish. Although expression of wildtype EGFP-tagged human <i>RLBP1</i> did not rescue the visual deficit, expression of zebrafish Cralbp to the RPE restored dim light vision, whereas zebrafish Cralbp harboring the human pathogenic p.R151Q mutation failed to do so. Together, these findings underscore the predominant role of RPE-expressed CRALBP in sustaining visual function under low-light conditions and establish a zebrafish platform for functional evaluation of <i>RLBP1</i> variants.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 12","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500600R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polyalanine Expansion in PABPN1 Alters the Structure and Dynamics of Its Nuclear Aggregates in Differentiated Muscle Cells","authors":"Sander D. Mallon,&nbsp;Erik Bos,&nbsp;Vahid Sheikhhassani,&nbsp;Milad Shademan,&nbsp;Lenard M. Voortman,&nbsp;Alireza Mashaghi,&nbsp;Thomas H. Sharp,&nbsp;Vered Raz","doi":"10.1096/fj.202501097R","DOIUrl":"https://doi.org/10.1096/fj.202501097R","url":null,"abstract":"<p>Intracellular protein aggregation is a hallmark of aging and contributes to pathology in some age-associated diseases. In hereditary adult-onset neuromuscular diseases (NMDs), protein aggregates play a key role in disease onset and progression. The wild-type Poly(A) binding protein nuclear 1 (PABPN1) forms benign nuclear aggregates, whereas a short trinucleotide expansion leads to the formation of pathogenic aggregates, a hallmark of Oculopharyngeal Muscular Dystrophy (OPMD). In OPMD, the mutant PABPN1 causes skeletal muscle weakness. So far, the structural differences between benign and pathogenic protein aggregates and their effects on muscle cell biology remain poorly understood. We employed an array of advanced imaging modalities to explore the morphological differences between nuclear aggregates formed by non-pathogenic and pathogenic PABPN1 variants. Through analyses spanning micro- to nanoscale, we identified distinct structural features of aggregates formed by wild-type and expanded PABPN1. We demonstrate that these differences were more pronounced in differentiated muscle cells compared to proliferating cells. We further linked the structural features of PABPN1 aggregates to muscle cell biology, namely alterations in mitochondrial function and proteasomal activity. Our findings provide new insights into the structural distinctions between pathogenic and non-pathogenic aggregates and their implications for cellular dysfunction in NMDs.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 12","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501097R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lnc056 Enhances Hair Follicle Stem Cells Proliferation by Binding Transcription Factor HNRNPUL1 to Up-Regulate TRIP6 Expression","authors":"Menghua Sui,&nbsp;Zhenyu Zhong,&nbsp;Lichan Tian,&nbsp;Shuangshuang Liang,&nbsp;Xinmiao Wang,&nbsp;Minghao Li,&nbsp;Xin Wang","doi":"10.1096/fj.202500381R","DOIUrl":"https://doi.org/10.1096/fj.202500381R","url":null,"abstract":"<div>\u0000 \u0000 <p>Hair follicles regenerate spontaneously through a cycle of anagen, catagen, and telogen, and this cycle is driven by hair follicle stem cells (HFSCs). Long non-coding RNAs (lncRNAs) have previously been implicated in hair follicle cycling processes. According to the previous lncRNA sequencing results of cashmere goats, an annotated lncRNA XR_310056.1, referred to as lnc056, was found to be differentially expressed during the hair follicle cycle. Here, the purpose of this study was to determine whether lnc056 affects the proliferation of HFSCs by regulating thyroid hormone receptor interactor 6 (<i>TRIP6</i>) expression in combination with the transcription factor HNRNPUL1. The expression of lnc056 in HFSCs was detected by RT-qPCR. HFSCs were then treated with lnc056 and <i>TRIP6</i> overexpressing adenovirus, si-HNRNPUL1, and si-TRIP6 to detect cell viability and proliferation. In addition, we investigated the binding between lnc056 and HNRNPUL1 or HNRNPUL1 and <i>TRIP6</i>. Finally, the biological function of lnc056 through the HNRNPUL1/<i>TRIP6</i> axis was verified by target gene recovery experiments. Lnc056 was expressed in the nuclei of HFSCs, and its overexpression promoted the proliferation of cells. Moreover, lnc056 was found to bind to the transcription factor HNRNPUL1 and promoted <i>TRIP6</i> expression. Furthermore, recovery assays demonstrated that lnc056 promoted the proliferation of HFSCs via the HNRNPUL1/<i>TRIP6</i> axis. In summary, the results of this study suggested that lnc056 up-regulated the expression of <i>TRIP6</i> by binding to the transcription factor HNRNPUL1, thereby accelerating the proliferation of HFSCs. This study enriches the molecular mechanism of lncRNA in the hair follicle cycle and provides a potential therapeutic target for hair loss.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 12","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367531","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":"Growth Arrest and DNA Damage Protein 45A Promotes PPRV Replication via the Downregulation of TBK1 Expression to Inhibit IFN-β Signaling Pathway","authors":"Haiyan Ding,&nbsp;Wenping Yang,&nbsp;Jinyan Wu,&nbsp;Junhuang Wu,&nbsp;Mengyi Wang,&nbsp;Jijun He,&nbsp;Ligang Yuan,&nbsp;Haixue Zheng,&nbsp;Youjun Shang,&nbsp;Dan Li","doi":"10.1096/fj.202500364R","DOIUrl":"https://doi.org/10.1096/fj.202500364R","url":null,"abstract":"<p>Peste des petits ruminants virus (PPRV) is a highly contagious pathogen that severely impacts goats and sheep due to its high contagiousness and pathogenicity. Viruses rely on host proteins for their pathogenicity and replication, but the specific mechanisms facilitating PPRV replication by host proteins remain poorly understood. In this study, we identified goat growth arrest and DNA damage protein 45A (GADD45A) as a positive regulator of PPRV replication. Overexpression of GADD45A enhances PPRV replication, while its knockdown significantly inhibits PPRV replication. Furthermore, GADD45A suppresses SeV- or Poly(I:C)-induced IFN-β promoter and ISRE activation in a dose-dependent manner, as well as the transcription of interferon-stimulated genes (ISGs). We also demonstrate that goat GADD45A interacts with TANK-binding kinase 1 (TBK1), leading to the downregulation of TBK1 expression. Co-immunoprecipitation and confocal microscopy confirmed that GADD45A interacts with the PPRV V protein. Both GADD45A and V synergistically inhibit IFN-β promoter activation and TBK1 expression, thereby promoting PPRV replication. Our findings suggest that GADD45A promotes PPRV replication by downregulating TBK1, offering new insights into host proteins that counteract innate immune responses during PPRV infection. These findings offer valuable insights into the role of host proteins in viral replication and immune evasion, shedding new light on how PPRV antagonizes innate immunity.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 12","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500364R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism of TGR5 in Ferroptosis of the Renal Tubular Epithelial Cells in Diabetes Mellitus and the Effect of Notoginsenoside Ft1","authors":"Xiang Xiao,&nbsp;Junlin Zhang,&nbsp;Yucheng Wu,&nbsp;Qing Yang,&nbsp;Yutong Zhou,&nbsp;Jia Yang,&nbsp;Yanlin Lang,&nbsp;Linli Cai,&nbsp;Xuegui Ju,&nbsp;Fang Liu","doi":"10.1096/fj.202402534R","DOIUrl":"https://doi.org/10.1096/fj.202402534R","url":null,"abstract":"<div>\u0000 \u0000 <p>TGR5 and its agonists have the role of regulating glycolipid metabolism. The ferroptosis of renal tubular epithelial cells (TECs) caused by glycolipid metabolism disorders participates in the process of DKD. This study aims to explore the relationship between TGR5 activation and the intervention of notoginsenoside Ft1 (Ft1) and the ferroptosis of diabetic renal TECs, as well as the possible molecular mechanism. By using adeno-associated virus 9 (AAV9) to overexpress TGR5 or Ft1 to intervene in db/db mice, the effects on renal injury and ferroptosis are observed. In addition, by inducing HK2 cells with high glucose and palmitic acid (HGPA) to simulate the injury model of diabetic TECs, the effects and molecular mechanisms of plasmid transfection for overexpressing TGR5, siRNA silencing TGR5 expression, and Ft1 intervention on ferroptosis are respectively observed. In db/db mice, overexpression of TGR5 or Ft1 intervention alleviated kidney damage, manifested as a reduction in proteinuria, mesangial matrix expansion, and an alleviation of tubular injury. In HK2 cultured with HGPA, overexpression of TGR5 or Ft1 intervention could both inhibit ferroptosis of TECs, while silencing the expression of TGR5 further promoted ferroptosis of TECs. The JNK signaling pathway played an important role in this process. These findings confirm the significant role of TGR5 activation or Ft1 intervention in diabetic TECs injury and ferroptosis, and imply that TGR5 may be a potential therapeutic target for diabetic TECs injury and ferroptosis, while Ft1 may be a potent drug for the treatment of DKD.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 12","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367398","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":"Extracellular Matrix Proximity Biotinylation Identifies Periostin as a PHEX Proteolytic Substrate","authors":"Chirada Dusadeemeelap,&nbsp;Takuma Matsubara,&nbsp;Shoichiro Kokabu,&nbsp;William N. Addison","doi":"10.1096/fj.202500635RR","DOIUrl":"https://doi.org/10.1096/fj.202500635RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Inactivating mutations in the PHEX gene lead to X-linked hypophosphatemia (XLH), which is characterized by impaired skeletal mineralization and low serum phosphate. Subsequent rickets and osteomalacia result in bone deformities and pseudofractures. A hallmark of XLH is an intrinsic defect in osteoblast function resulting in altered bone matrix composition typified by the local accumulation of extracellular matrix proteins and peptide fragments. PHEX is a membrane-bound endopeptidase expressed in osteoblasts and osteocytes. Little is known about PHEX proteolytic substrates or the protein–protein interactions governing PHEX function. Classical affinity purification approaches are challenging in studies of the extracellular environment. Here, we developed an approach for unbiased identification of the extracellular proximal interactome of PHEX in osteoblasts using proximity-dependent biotin identification combined with affinity purification and mass spectrometry. By tagging the PHEX extracellular domain with BioID2 biotin ligase, we labeled and unveiled a PHEX proximity network consisting of 39 high-confidence proteins. Notably, several candidates with documented roles in bone morphogenesis and matrix organization were identified. We validated interaction of PHEX with periostin, a bone-matrix protein associated with collagen-fibril organization, cell adhesion and cell migration. Co-transfection experiments and cell-free enzyme cleavage assays revealed proteolytic cleavage of secreted periostin by PHEX. In conclusion, BioID2 is a powerful strategy to explore cell-matrix relationships in osteoblasts. These results present a novel map of the PHEX interactome and serve as a valuable resource for unraveling the mechanisms underlying PHEX function and XLH.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 12","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144331908","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":"HELQ Maintains Genome Stability of Primordial Germ Cells by Inhibiting LINE-1 Expression","authors":"Lili Cao,&nbsp;Jiayi Ren,&nbsp;Zhaojie Kong,&nbsp;Mengchun Hu,&nbsp;Yaxuan Zhang,&nbsp;Zi-Jiang Chen,&nbsp;Yingying Qin,&nbsp;Yajuan Yang,&nbsp;Shidou Zhao","doi":"10.1096/fj.202403260R","DOIUrl":"https://doi.org/10.1096/fj.202403260R","url":null,"abstract":"<p>The DNA helicase HELQ is involved in homologous recombination repair, interstrand cross-link repair, and replication stress response. Its functional defects are associated with infertility and abnormal gametogenesis. However, the specific mechanisms of HELQ in the development of germ cells remain to be elucidated. Here, we uncovered that HELQ deficiency led to proliferation defects of primordial germ cells (PGCs) in mouse embryos, thus compromising the establishment of reproductive reserve. Mechanistically, we found that HELQ interacted with the H3K9me3 demethylase KDM4B, and the absence of HELQ led to a marked increase in both total and chromatin-bound protein levels of KDM4B, resulting in reduced H3K9me3 levels in the region of the retrotransposon LINE-1, which triggered its high expression and subsequently caused DNA damage accumulation. Moreover, the developmental defects of HELQ-deficient PGCs were alleviated by inhibition of retrotransposition. These results indicate that HELQ maintains the genome stability of PGCs by repressing LINE-1 expression. Our study reveals a critical role of HELQ in PGC development and provides new insights into reproductive disorders caused by defects in DNA damage response factors.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 12","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202403260R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144331856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}