Cellular and Molecular Life Sciences最新文献

Mutated sigma-1R disrupts cell homeostasis in dHMN patient cells.

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-04-09 DOI: 10.1007/s00018-025-05676-y

Sofia Zanin, Francesco Ciscato, Antonio Petrucci, Annalisa Botta, Federico Chiossi, Giovanni Vazza, Rosario Rizzuto, Giorgia Pallafacchina

{"title":"Mutated sigma-1R disrupts cell homeostasis in dHMN patient cells.","authors":"Sofia Zanin, Francesco Ciscato, Antonio Petrucci, Annalisa Botta, Federico Chiossi, Giovanni Vazza, Rosario Rizzuto, Giorgia Pallafacchina","doi":"10.1007/s00018-025-05676-y","DOIUrl":"https://doi.org/10.1007/s00018-025-05676-y","url":null,"abstract":"Hereditary-Motor-Neuropathies (dHMNs) are clinically and genetically heterogeneous neurological disorders characterized by degeneration of peripheral motoneurons. We previously identified two sigma-1 receptor (Sigma-1R) variants (p.E138Q; p.E150K) in dHMN Italian patients that behave as \"loss-of-function\" mutations in neuroblastoma cell lines. Here, we characterize the functional effects of Sigma-1R mutation in primary fibroblasts from homozygous patients bearing the E150K mutation, and matched controls, by performing biochemical, gene expression, immunofluorescence and Ca2+ imaging analysis. Our results show that Sigma-1R expression and distribution is significantly altered in patient fibroblasts. Moreover, patient cells present a general derangement of cell homeostasis as revealed by impairment of global Ca2+ dynamics, disorganization of the ER-mitochondria tethers, enhancement of the autophago-lysosomal pathway and blunting of mitochondrial aerobic metabolism compared to controls. These findings highlight the crucial role of Sigma-1R in the maintenance of cell and protein homeostasis, inter-organelle communication and intracellular Ca2+ signalling, supporting the notion that Sigma-1R is protective for motor neuron activity and its down-regulation and/or loss-of-function, as in the case of the E150K mutation, might play the key role in the neuronal degeneration in dHMN patients.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"151"},"PeriodicalIF":6.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810674","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}

引用次数: 0

Circular RNA circSTX12 regulates osteo-adipogenic balance and proliferation of BMSCs in senile osteoporosis.

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-04-07 DOI: 10.1007/s00018-025-05684-y

Huimin Gu, Wenhui Yu, Pei Feng, Chenying Zeng, Qian Cao, Fenglei Chen, Ziming Wang, Huiyong Shen, Yanfeng Wu, Shan Wang

{"title":"Circular RNA circSTX12 regulates osteo-adipogenic balance and proliferation of BMSCs in senile osteoporosis.","authors":"Huimin Gu, Wenhui Yu, Pei Feng, Chenying Zeng, Qian Cao, Fenglei Chen, Ziming Wang, Huiyong Shen, Yanfeng Wu, Shan Wang","doi":"10.1007/s00018-025-05684-y","DOIUrl":"10.1007/s00018-025-05684-y","url":null,"abstract":"Increased adipogenic differentiation and decreased osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) along with slow self-renewal are pivotal causes for decreased bone formation in senile osteoporosis. Circular RNAs (circRNAs) play important roles in cell proliferation and differentiation, and are closely related to osteoporosis. Whether circRNAs orchestrate the adipo-osteogenic balance and the proliferation of BMSCs in osteoporosis remains unclear. We found in this study that circSTX12 was abnormally upregulated in bone sections from osteoporosis patients and in BMSCs from aged mice, as well as in later-generation human BMSCs in culture. Knockdown of circSTX12 in BMSCs resulted in enhanced osteogenesis, decreased adipogenesis, and increased proliferation capacity; circSTX12 overexpression had the opposite effect. RNA pull-down and mass spectrometry revealed the interactions between circSTX12 with CBL and LMO7. At the molecular level, circSTX12 regulated cell fate in BMSCs by competitively binding to CBL, reducing the ubiquitination-mediated degradation of MST1 and thereby activating the Hippo pathway, a key regulator of adipo-osteogenic balance. Knockdown of circSTX12 promoted the nuclear localization of YAP. In addition, our findings suggest that LMO7 mediates circSTX12-induced BMSCs proliferation by regulating the transcription of CCNA2, CCNH, and CCND1. In vivo, injection of antisense oligonucleotides (ASOs) to knockdown circSTX12 promoted bone formation in aged mice. Our results provide evidence for circSTX12 as a regulator of adipo-osteogenic differentiation and proliferation of BMSCs through binding to CBL and LMO7, respectively. Targeting circSTX12 may be a novel approach for osteoporosis treatment.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"149"},"PeriodicalIF":6.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794721","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}

引用次数: 0

Dietary advanced glycation end-products exacerbate sarcopenia onset by activating apoptosis through PRMT1-mediated CRTC3 arginine methylation.

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-04-07 DOI: 10.1007/s00018-025-05657-1

Tian-Jin Huang, Shu Shang, Qin Wan, Qiang Li, Yang-Jingsi Li, Jin-Na Zheng, Fa-Xiu Chen

{"title":"Dietary advanced glycation end-products exacerbate sarcopenia onset by activating apoptosis through PRMT1-mediated CRTC3 arginine methylation.","authors":"Tian-Jin Huang, Shu Shang, Qin Wan, Qiang Li, Yang-Jingsi Li, Jin-Na Zheng, Fa-Xiu Chen","doi":"10.1007/s00018-025-05657-1","DOIUrl":"10.1007/s00018-025-05657-1","url":null,"abstract":"Background: Sarcopenia, the age-related decline in muscle mass and function, poses a major health risk to the elderly population. Although dietary advanced glycation end-products (AGEs) have been implicated in worsening sarcopenia, the precise molecular mechanisms remain unclear.Methods: A sarcopenia animal model was established by feeding a high AGE diet to C57BL/6 mice. Muscle function and mass were assessed using grip strength tests, and rotarod tests. Proteomic analysis was used to identify differentially expressed proteins. Immunoprecipitation, mass spectrometry, and co-immunoprecipitation were employed to investigate protein interactions both in vivo and in vitro. Quantitative reverse transcription PCR and Western blotting were conducted to measure gene and protein expression levels.Results: Our results revealed that dietary AGEs accelerated the onset of sarcopenia in mice by triggering apoptosis. Proteomic analysis showed a marked upregulation of protein arginine methyltransferase 1 (PRMT1) in the muscle tissues of mice fed a high AGE diet. PRMT1 mediated the arginine methylation of CREB-regulated transcription coactivator 3 (CRTC3) at the R534 site within its transactivation domain, leading to CRTC3 activation. The activated CRTC3, together with Forkhead box O3a (FOXO3a), transactivated the BAX (BCL2 associated X) gene, initiating Bax downstream signaling, promoting apoptosis in muscle cells, and contributing to muscle atrophy. Inhibition of PRMT1 prevented CRTC3 methylation and suppressed Bax-mediated apoptotic signaling in vitro. Moreover, in vivo treatment with PRMT1 and Bax inhibitors significantly attenuated AGE-induced sarcopenia in mice.Conclusion: PRMT1-mediated CRTC3 arginine methylation plays a critical role in AGE-induced sarcopenia and suggests potential therapeutic targets for preventing sarcopenia progression.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"142"},"PeriodicalIF":6.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794734","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}

引用次数: 0

Heat shock protein 60 manipulates Foot-and-Mouth disease virus replication by regulating mitophagy.

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-04-07 DOI: 10.1007/s00018-025-05623-x

Jianli Tang, Sahibzada Waheed Abdullah, Shiqi Sun, Huichen Guo

{"title":"Heat shock protein 60 manipulates Foot-and-Mouth disease virus replication by regulating mitophagy.","authors":"Jianli Tang, Sahibzada Waheed Abdullah, Shiqi Sun, Huichen Guo","doi":"10.1007/s00018-025-05623-x","DOIUrl":"10.1007/s00018-025-05623-x","url":null,"abstract":"Mitochondria serve as the hubs of cellular signaling, energetics, and redox balance under physiological conditions. Mitochondria play an essential role in defending against pathogenic infections upon virus invasion. As a critical intracellular physiological process, mitophagy is crucial for maintaining mitochondrial homeostasis. Accumulating evidence suggests that mitophagy contributes to modulating viral infection. In our previous study, we reported that heat shock protein 60 (HSP60) is involved in orchestrating autophagy; however, the underlying mechanisms remain elusive. Here, we examined the role of HSP60 in priming mitophagy to regulate foot-and-mouth disease virus (FMDV) replication. We first reported that mitophagy was elicited post-FMDV infection and further restricted FMDV replication. Regarding HSP60, our results showed that HSP60 depletion triggered Parkin-dependent mitophagy via activating dynamin-related protein 1 (Drp1) phosphorylation at Ser616 and promoting Drp1 translocation to mitochondria. Furthermore, calmodulin-dependent protein kinase II (CaMKII) was essential for phosphorylating Drp1 at Ser616 in HSP60-depleted cells. Taken together, HSP60 manipulates FMDV replication by governing mitophagy. Importantly, HSP60 could be a promising antiviral target for controlling FMDV infection.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"141"},"PeriodicalIF":6.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794736","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}

引用次数: 0

Adenine base editing of CFTR using receptor targeted nanoparticles restores function to G542X cystic fibrosis airway epithelial cells.

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-04-07 DOI: 10.1007/s00018-025-05587-y

Isabelle Rose, Miriam Greenwood, Matthew Biggart, Natalie Baumlin, Robert Tarran, Stephen L Hart, Deborah L Baines

{"title":"Adenine base editing of CFTR using receptor targeted nanoparticles restores function to G542X cystic fibrosis airway epithelial cells.","authors":"Isabelle Rose, Miriam Greenwood, Matthew Biggart, Natalie Baumlin, Robert Tarran, Stephen L Hart, Deborah L Baines","doi":"10.1007/s00018-025-05587-y","DOIUrl":"10.1007/s00018-025-05587-y","url":null,"abstract":"The cystic fibrosis (CF) causing variant G542X harbours a premature translation stop signal in the cystic fibrosis transmembrane conductance regulator (CFTR) mRNA. This results in nonsense-mediated decay and loss of functional CFTR protein which leads to defective anion transport and the development of CF disease pathology. Currently available CF modulator therapies cannot be used to treat this variant. We used an adenine base editor (ABE8e Cas9) and guide RNA (sgRNA)/enhanced green fluorescent protein (EGFP) plasmids encapsulated in receptor targeted nanoparticles (RTN), delivered to Bmi-1 transduced basal human CF nasal epithelial cells harbouring the homozygous CFTR G542X variant, to convert the stop codon to G542R, a variant which is amenable to modulator therapy. ABE resulted in 17% of alleles edited to G542R and further selection of GFP fluorescent cells by FACS liberated a population with 52% G542R edited alleles with no editing of neighbouring adenines (A) and few off target edits using a gRNA homology-based approach. In cells differentiated at air-liquid-interface (ALI), 17% and 52% editing of CFTR G542X increased mRNA abundance. 52% editing alone or 17% and 52% editing of CFTR G542X plus treatment with CFTR modulators (VX-445/VX-661/VX-770; ETI/Trikafta/Kaftrio) increased epithelial CFTR protein expression, CFTR protein band C abundance, CFTR172 inhibitable anion transport, and changes in airway surface liquid height and pH in response to vasoactive intestinal peptide (VIP) stimulation. Epithelial scratch repair speed and directionality was also improved. These data provide proof-of-concept that ABE of G542X to G542R in human CF airway epithelial cells could provide a feasible therapy for this variant.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"144"},"PeriodicalIF":6.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794717","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}

引用次数: 0

Immunogenicity and protective efficacy of an inactivated bivalent vaccine containing two recombinant H1N1 and H3N2 swine influenza virus strains.

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-04-07 DOI: 10.1007/s00018-025-05674-0

Heng Zhang, Xu Chen, Dongying Liu, Xinyu Liu, Yifan Ge, Yani Sun, Xiaoyue Zhang, Guangen Hao, Zhaoyang Li, Qingqing Song, Lei Wang, Zhao Wang, Huanliang Yang, Qing Pan, Qin Zhao

{"title":"Immunogenicity and protective efficacy of an inactivated bivalent vaccine containing two recombinant H1N1 and H3N2 swine influenza virus strains.","authors":"Heng Zhang, Xu Chen, Dongying Liu, Xinyu Liu, Yifan Ge, Yani Sun, Xiaoyue Zhang, Guangen Hao, Zhaoyang Li, Qingqing Song, Lei Wang, Zhao Wang, Huanliang Yang, Qing Pan, Qin Zhao","doi":"10.1007/s00018-025-05674-0","DOIUrl":"10.1007/s00018-025-05674-0","url":null,"abstract":"The wild-type H1N1 and H3N2 swine influenza virus (SIV) strains are unsuitable for vaccine production because of high lethality in chicken embryos and low reproductive titers. This study developed recombinant H1N1-Re1 and H3N2-Re1 strains via HA and NA genes from the wild-type H1N1 SW/GX/755/17 and H3N2 SW/GX/1659/17 strains combined with six internal genes from the H1N1 A/PR/8/34 strain. The recombinant viruses demonstrated typical cytopathic effects in MDCK cells, and the presence of viral particles was confirmed via electron microscopy. Growth curve analysis revealed titers of 108.31 and 108.17 EID50 per 100 µL for H1N1-Re1 and H3N2-Re1, respectively, within 72-96 h postinoculation. Virus stocks were used to produce a bivalent inactivated vaccine. After two immunizations, hemagglutination inhibition titers in piglets were significantly greater than those induced by commercial vaccines and were sustained from 5 to 29 weeks postimmunization. Upon challenge with virulent wild-type SIV strains, viral isolation occurred in all pigs in the PBS group (5/5 protection), whereas no virus was detected in the bivalent vaccine group (0/5). In contrast, the commercial vaccine group had a viral isolation rate of 1/5. Pathological examination revealed severe pulmonary lesions in the PBS group, mild changes in the commercial vaccine group (1/5), and normal lung morphology in the bivalent vaccine group. This study demonstrated the successful application of an eight-plasmid reverse genetics system to develop recombinant vaccine strains with enhanced immunogenicity and replication efficiency. The bivalent inactivated vaccine provides prolonged and complete protection against H1N1 and H3N2 SIV strains, offering a robust tool for controlling evolving SIV variants.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"150"},"PeriodicalIF":6.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794739","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}

引用次数: 0

Loss of NgBR causes neuronal damage through decreasing KAT7-mediated RFX1 acetylation and FGF1 expression.

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-04-07 DOI: 10.1007/s00018-025-05660-6

Yuwei Hu, Yanni Ma, Lele Liu, Yan Hong, Guanghui Wang, Beisha Tang, Jifeng Guo, Peng Yang, Ying Cao, Haigang Ren

{"title":"Loss of NgBR causes neuronal damage through decreasing KAT7-mediated RFX1 acetylation and FGF1 expression.","authors":"Yuwei Hu, Yanni Ma, Lele Liu, Yan Hong, Guanghui Wang, Beisha Tang, Jifeng Guo, Peng Yang, Ying Cao, Haigang Ren","doi":"10.1007/s00018-025-05660-6","DOIUrl":"10.1007/s00018-025-05660-6","url":null,"abstract":"Parkinson's disease (PD) is a common neurodegenerative movement disorder characterized by dopaminergic neuron loss in the substantia nigra pars compacta and striatal dopamine depletion. The NUS1 gene, which encodes the neurite outgrowth inhibitor B receptor (NgBR), has been recently identified as a novel risk gene for PD. However, its roles and mechanism in neurodegeneration are still unclear. Here, we demonstrate that NgBR deficiency triggers neuronal damage through a novel KAT7/RFX1/FGF1 axis. RNA sequencing and experimental verification revealed that NgBR depletion downregulates expression and secretion of fibroblast growth factor 1 (FGF1), which led to inactivation of the PI3K/AKT signaling pathway. Mechanistically, NgBR deletion suppresses lysine acetyltransferase 7 (KAT7) expression, impairing KAT7-mediated acetylation of regulatory factor X1 (RFX1), a transcriptional repressor for FGF1. This stabilized RFX1 by blocking its proteasomal degradation, thereby suppressing FGF1 transcription. Crucially, exogenous FGF1 rescued AKT signaling and mitigated neuronal damage in NgBR-deficient models. Our findings establish NgBR-KAT7-RFX1 as a regulatory axis controlling FGF1-dependent neuroprotection, which promotes the understanding of PD pathogenesis and highlights FGF1 supplementation as a potential therapeutic strategy.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"140"},"PeriodicalIF":6.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794744","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}

引用次数: 0

Micro-proteomics reveals distinct protein profiles and SPARC/FGF2/CDH1 regulation of human Sertoli cells between Sertoli cell-only syndrome and normal men.

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-04-07 DOI: 10.1007/s00018-025-05678-w

Li Du, Yinghong Cui, Wei Chen, Chunyun Li, Zuping He

{"title":"Micro-proteomics reveals distinct protein profiles and SPARC/FGF2/CDH1 regulation of human Sertoli cells between Sertoli cell-only syndrome and normal men.","authors":"Li Du, Yinghong Cui, Wei Chen, Chunyun Li, Zuping He","doi":"10.1007/s00018-025-05678-w","DOIUrl":"10.1007/s00018-025-05678-w","url":null,"abstract":"Sertoli cell-only syndrome (SCOS) is one of the most severe non-obstructive azoospermia (NOA) types, since only Sertoli cells with not any male germ cells exist with the seminiferous tubules. As such, it is of particular significance to elucidate molecular mechanisms underlying SCOS for improving the diagnosis and treatment strategies for this disease. Due to the difficulties in obtaining sufficient human testicular tissues and the limited availability of human cells, the traditional proteomics is inadequate for comparing the differences in large scale of protein expression patterns of human Sertoli cells between SCOS and normal men. To solve this issue on the requirement of large amount of cell numbers, we employed micro-proteomics to reveal distinct global protein expression profiles of human Sertoli cells between SCOS and obstructive azoospermia (OA) with normal spermatogenesis utilizing single human Sertoli cells. We found a significant downregulation of proteins involved in cell adhesion pathways in SCOS Sertoli cells, whereas proteins related to apoptosis were markedly upregulated. Interestingly, we identified the lower expression of SPARC (secreted protein acidic and rich in cysteine) and the higher expression of FGF2 (fibroblast growth factor 2) in human Sertoli cells of the SCOS compared to normal men. SPARC silencing led to upregulation of FGF2 in human Sertoli cells, and SPARC may be associated with the occurrence of SCOS and serves as a reliable marker for the diagnosis of this disease. This study thus comprehensively offers the proteomic landscape of human Sertoli cells in the testes of SCOS patients and it sheds a novel insight into the pathogenesis of SCOS.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"146"},"PeriodicalIF":6.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794749","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}

引用次数: 0

S146 and M148 within the mature chain domain of PSMB4 are crucial for degrading PRRSV nsp1α.

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-04-07 DOI: 10.1007/s00018-025-05679-9

Binghua Chen, Yongjie Chen, Zhan He, Yanfei Pan, Yunyan Luo, Jiecong Yan, Fangfang Li, Chunhe Guo

{"title":"S146 and M148 within the mature chain domain of PSMB4 are crucial for degrading PRRSV nsp1α.","authors":"Binghua Chen, Yongjie Chen, Zhan He, Yanfei Pan, Yunyan Luo, Jiecong Yan, Fangfang Li, Chunhe Guo","doi":"10.1007/s00018-025-05679-9","DOIUrl":"10.1007/s00018-025-05679-9","url":null,"abstract":"Porcine reproductive and respiratory syndrome virus (PRRSV) is a single-stranded positive-sense RNA virus with an envelope. It-encoded non-structural protein 1α (nsp1α) plays a key role in evading host immune responses. Exploring the interaction between host factors and PRRSV nsp1α is crucial for understanding the mechanism of virus immune escape and virus control. Here, we constructed a cDNA library using porcine lung tissues and identified 33 potential host proteins interacting with viral nsp1α using yeast two-hybrid (Y2H) screening. These interactions were further analyzed using Gene Ontology and KEGG pathway analysis. Confocal microscopy revealed that proteasome subunit beta type-4 (PSMB4), carnosine dipeptidase 2 (CNDP2) and poly(rC) binding protein 1 (PCBP1) colocalized with viral nsp1α. The interaction between PSMB4 and nsp1α was further confirmed by Y2H and co-immunoprecipitation. PRRSV infection did not affect PSMB4 expression in both Marc-145 cells and porcine alveolar macrophages (PAMs). Overexpression of PSMB4 reduced nsp1α protein levels in a dose-dependent manner and decreased the accumulation of both viral N and nsp1α proteins in the context of PRRSV infection, while its knockdown promoted PRRSV replication. These data suggest that PSMB4 is a host restriction factor for PRRSV. Structure prediction and truncated mutant assays found that S146 and M148 within the mature chain domain of PSMB4 were crucial for binding and degrading nsp1α. These findings suggest that PRRSV nsp1α interacts with host proteins, with PSMB4 specifically binding to degrade nsp1α, thereby inhibiting PRRSV replication.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"148"},"PeriodicalIF":6.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794769","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}

引用次数: 0

Syndecan-3 positively regulates the pro-inflammatory function of macrophages.

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-04-07 DOI: 10.1007/s00018-025-05649-1

So Young Lee, Endika Prieto-Fernández, Leire Egia-Mendikute, Asier Antoñana-Vildosola, Paloma Velasco-Beltrán, Alexandre Bosch, Borja Jimenez-Lasheras, Ander de Blas, Jone Etxaniz-Diaz de Durana, Eunate Valdaliso-Díez, Laura Bozal-Basterra, Amaia Ercilla, José Ezequiel Martin, Arkaitz Carracedo, Alena Gros, Ana M Aransay, Asís Palazón, Lorena Pérez-Gutiérrez

{"title":"Syndecan-3 positively regulates the pro-inflammatory function of macrophages.","authors":"So Young Lee, Endika Prieto-Fernández, Leire Egia-Mendikute, Asier Antoñana-Vildosola, Paloma Velasco-Beltrán, Alexandre Bosch, Borja Jimenez-Lasheras, Ander de Blas, Jone Etxaniz-Diaz de Durana, Eunate Valdaliso-Díez, Laura Bozal-Basterra, Amaia Ercilla, José Ezequiel Martin, Arkaitz Carracedo, Alena Gros, Ana M Aransay, Asís Palazón, Lorena Pérez-Gutiérrez","doi":"10.1007/s00018-025-05649-1","DOIUrl":"10.1007/s00018-025-05649-1","url":null,"abstract":"The tumour microenvironment (TME) is a highly structured ecosystem that surrounds a tumour and plays a crucial role in tumorigenesis. As one of the most abundant cell types in the TME, tumour-associated-macrophages (TAMs) can promote disease progression and resistance to therapy. Syndecan-3 (SDC3) is a cell-surface heparan sulphate proteoglycan expressed by TAMs, although its functional relevance in these cells remains unknown. Here, we demonstrated that pro-inflammatory cytokines drive the expression of SDC3 on the cell surface of macrophages. Genetic ablation of SDC3 in macrophages led to aberrant proliferation, adhesion and expression of CD40 and CD86 surface markers. Moreover, SDC3 defective macrophages exhibited distinctive gene expression patterns, leading to impaired tumour cell phagocytosis and increased tumour cell proliferation. Mechanistically, a decrease in the secretion of pro-inflammatory cytokines was observed in SDC3 KO macrophages, concomitant with impaired T cell effector functions. Additionally, a higher angiogenic capacity was observed in endothelial cells when co-cultured with macrophages deficient for SDC3, possibly mediated through an increased release of VEGFA, PECAM-1 and IL-8 by SDC3 KO cells. Collectively, we have identified SDC3 as a modulator of macrophage functions aiming at supporting a pro-inflammatory and anti-tumour phenotype in these cells.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"145"},"PeriodicalIF":6.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794813","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}

引用次数: 0