Cellular and Molecular Life Sciences最新文献_第2页

The phospholamban R14del generates pathogenic aggregates by impairing autophagosome-lysosome fusion. 磷脂酰胆碱 R14del 通过损害自噬体-溶酶体融合产生致病性聚集体。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-11-11 DOI: 10.1007/s00018-024-05471-1

Elizabeth Vafiadaki, Evangelia G Kranias, Aristides G Eliopoulos, Despina Sanoudou

{"title":"The phospholamban R14del generates pathogenic aggregates by impairing autophagosome-lysosome fusion.","authors":"Elizabeth Vafiadaki, Evangelia G Kranias, Aristides G Eliopoulos, Despina Sanoudou","doi":"10.1007/s00018-024-05471-1","DOIUrl":"10.1007/s00018-024-05471-1","url":null,"abstract":"Phospholamban (PLN) plays a crucial role in regulating sarcoplasmic reticulum (SR) Ca2+ cycling and cardiac contractility. Mutations within the PLN gene have been detected in patients with cardiomyopathy, with the heterozygous variant c.40_42delAGA (p.R14del) of PLN being the most prevalent. Investigations into the mechanisms underlying the pathology of PLN-R14del have revealed that cardiac cells from affected patients exhibit pathological aggregates containing PLN. Herein, we performed comprehensive molecular and cellular analyses to delineate the molecular aberrations associated with the formation of these aggregates. We determined that PLN aggregates contain autophagic proteins, indicating inefficient degradation via the autophagy pathway. Our findings demonstrate that the expression of PLN-R14del results in diminished autophagic flux due to impaired fusion between autophagosomes and lysosomes. Mechanistically, this defect is linked to aberrant recruitment of key membrane fusion proteins to autophagosomes, which is mediated in part by changes in Ca2+ homeostasis. Collectively, these results highlight a novel function of PLN-R14del in regulating autophagy, that may contribute to the formation of pathogenic aggregates in patients with cardiomyopathy. Prospective strategies tailored to ameliorate impaired autophagy may hold promise against PLN-R14del disease.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"450"},"PeriodicalIF":6.2,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615966","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}

引用次数: 0

Dapagliflozin targets SGLT2/SIRT1 signaling to attenuate the osteogenic transdifferentiation of vascular smooth muscle cells. Dapagliflozin靶向SGLT2/SIRT1信号，抑制血管平滑肌细胞的成骨转分化。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-11-09 DOI: 10.1007/s00018-024-05486-8

Long Li, Huimin Liu, Quanyou Chai, Junyi Wei, Yuqiao Qin, Jingyao Yang, He Liu, Jia Qi, Chunling Guo, Zhaoyang Lu

{"title":"Dapagliflozin targets SGLT2/SIRT1 signaling to attenuate the osteogenic transdifferentiation of vascular smooth muscle cells.","authors":"Long Li, Huimin Liu, Quanyou Chai, Junyi Wei, Yuqiao Qin, Jingyao Yang, He Liu, Jia Qi, Chunling Guo, Zhaoyang Lu","doi":"10.1007/s00018-024-05486-8","DOIUrl":"10.1007/s00018-024-05486-8","url":null,"abstract":"Vascular calcification is a complication that is frequently encountered in patients affected by atherosclerosis, diabetes, and chronic kidney disease (CKD), and that is characterized by the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). At present, there remains a pressing lack of any effective therapies that can treat this condition. The sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin (DAPA) has shown beneficial effects in cardiovascular disease. The role of this inhibitor in the context of vascular calcification, however, remains largely uncharacterized. Our findings revealed that DAPA treatment was sufficient to alleviate in vitro and in vivo osteogenic transdifferentiation and vascular calcification. Interestingly, our study demonstrated that DAPA exerts its anti-calcification effects on VSMCs by directly targeting SGLT2, with the overexpression of SGLT2 being sufficient to attenuate these beneficial effects. DAPA was also able to limit the glucose levels and NAD+/NADH ratio in calcified VSMCs, upregulating sirtuin 1 (SIRT1) in a caloric restriction (CR)-dependent manner. The SIRT1-specific siRNA and the SIRT1 inhibitor EX527 attenuated the anti-calcification effects of DAPA treatment. DAPA was also to drive SIRT1-mediated deacetylation and consequent degradation of hypoxia-inducible factor-1α (HIF-1α). The use of cobalt chloride and proteasome inhibitor MG132 to preserve HIF-1α stability mitigated the anti-calcification activity of DAPA. These analyses revealed that the DAPA/SGLT2/SIRT1 axis may therefore represent a viable novel approach to treating vascular calcification, offering new insights into how SGLT2 inhibitors may help prevent and treat vascular calcification.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"448"},"PeriodicalIF":6.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616013","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}

引用次数: 0

The lemur tail kinase family in neuronal function and disfunction in neurodegenerative diseases. 狐猴尾激酶家族在神经退行性疾病中的神经元功能和功能障碍。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-11-09 DOI: 10.1007/s00018-024-05480-0

Angelique Larose, Christopher C J Miller, Gábor M Mórotz

{"title":"The lemur tail kinase family in neuronal function and disfunction in neurodegenerative diseases.","authors":"Angelique Larose, Christopher C J Miller, Gábor M Mórotz","doi":"10.1007/s00018-024-05480-0","DOIUrl":"10.1007/s00018-024-05480-0","url":null,"abstract":"The complex neuronal architecture and the long distance of synapses from the cell body require precisely orchestrated axonal and dendritic transport processes to support key neuronal functions including synaptic signalling, learning and memory formation. Protein phosphorylation is a major regulator of both intracellular transport and synaptic functions. Some kinases and phosphatases such as cyclin dependent kinase-5 (cdk5)/p35, glycogen synthase kinase-3β (GSK3β) and protein phosphatase-1 (PP1) are strongly involved in these processes. A primary pathological hallmark of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal dementia, is synaptic degeneration together with disrupted intracellular transport. One attractive possibility is that alterations to key kinases and phosphatases may underlie both synaptic and axonal transport damages. The brain enriched lemur tail kinases (LMTKs, formerly known as lemur tyrosine kinases) are involved in intracellular transport and synaptic functions, and are also centrally placed in cdk5/p35, GSK3β and PP1 signalling pathways. Loss of LMTKs is documented in major neurodegenerative diseases and thus can contribute to pathological defects in these disorders. However, whilst function of their signalling partners became clearer in modulating both synaptic signalling and axonal transport progress has only recently been made around LMTKs. In this review, we describe this progress with a special focus on intracellular transport, synaptic functions and neurodegenerative diseases.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"447"},"PeriodicalIF":6.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615949","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}

引用次数: 0

BCAS2 and hnRNPH1 orchestrate alternative splicing for DNA double-strand break repair and synapsis in meiotic prophase I. BCAS2 和 hnRNPH1 在减数分裂原期 I 中协调 DNA 双链断裂修复和突触的替代剪接。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-11-09 DOI: 10.1007/s00018-024-05479-7

Longjie Sun, Rong Ye, Changchang Cao, Zheng Lv, Chaofan Wang, Xiaomei Xie, Xuexue Chen, Xiaohong Yao, Shuang Tian, Lu Yan, Yujing Shao, Sheng Cui, Chen Chen, Yuanchao Xue, Lei Li, Juan Chen, Jiali Liu

{"title":"BCAS2 and hnRNPH1 orchestrate alternative splicing for DNA double-strand break repair and synapsis in meiotic prophase I.","authors":"Longjie Sun, Rong Ye, Changchang Cao, Zheng Lv, Chaofan Wang, Xiaomei Xie, Xuexue Chen, Xiaohong Yao, Shuang Tian, Lu Yan, Yujing Shao, Sheng Cui, Chen Chen, Yuanchao Xue, Lei Li, Juan Chen, Jiali Liu","doi":"10.1007/s00018-024-05479-7","DOIUrl":"10.1007/s00018-024-05479-7","url":null,"abstract":"Understanding the intricacies of homologous recombination during meiosis is crucial for reproductive biology. However, the role of alternative splicing (AS) in DNA double-strand breaks (DSBs) repair and synapsis remains elusive. In this study, we investigated the impact of conditional knockout (cKO) of the splicing factor gene Bcas2 in mouse germ cells, revealing impaired DSBs repair and synapsis, resulting in non-obstructive azoospermia (NOA). Employing crosslinking immunoprecipitation and sequencing (CLIP-seq), we globally mapped BCAS2 binding sites in the testis, uncovering its predominant association with 5' splice sites (5'SS) of introns and a preference for GA-rich regions. Notably, BCAS2 exhibited direct binding and regulatory influence on Trp53bp1 (codes for 53BP1) and Six6os1 through AS, unveiling novel insights into DSBs repair and synapsis during meiotic prophase I. Furthermore, the interaction between BCAS2, hnRNPH1, and SRSF3 was discovered to orchestrate Trp53bp1 expression via AS, underscoring its role in meiotic prophase I DSBs repair. In summary, our findings delineate the indispensable role of BCAS2-mediated post-transcriptional regulation in DSBs repair and synapsis during male meiosis. This study provides a comprehensive framework for unraveling the molecular mechanisms governing the post-transcriptional network in male meiosis, contributing to the broader understanding of reproductive biology.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"449"},"PeriodicalIF":6.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616011","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}

引用次数: 0

PARylation of GCN5 by PARP1 mediates its recruitment to DSBs and facilitates both HR and NHEJ Repair. PARP1 对 GCN5 的 PAR 化介导了其对 DSB 的招募，并促进了 HR 和 NHEJ 修复。

IF 5.3 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-11-07 DOI: 10.1007/s00018-024-05469-9

Debashmita Sarkar, Amartya Chakraborty, Shaina Mandi, Shilpee Dutt

{"title":"PARylation of GCN5 by PARP1 mediates its recruitment to DSBs and facilitates both HR and NHEJ Repair.","authors":"Debashmita Sarkar, Amartya Chakraborty, Shaina Mandi, Shilpee Dutt","doi":"10.1007/s00018-024-05469-9","DOIUrl":"10.1007/s00018-024-05469-9","url":null,"abstract":"Efficient DNA double strand break (DSB) repair is necessary for genomic stability and determines efficacy of DNA damaging cancer therapeutics. Spatiotemporal dynamics and post-translational modifications of repair proteins at DSBs dictate repair efficacy. Here, we identified a non-canonical function of GCN5 in regulating both HR and NHEJ repair post genotoxic stress. Mechanistically, genotoxic stress induced GCN5 recruitment to DSBs. GCN5 PARylation by PARP1 was essential for its recruitment, acetyltransferase activity and DSB repair function. Liquid chromatography-mass spectrometry (LC-MS) identified DNA-PKcs as part of GCN5 interactome. In-vitro acetyltransferase assays revealed that GCN5 acetylates DNA-PKcs at K3241 residue, a prerequisite for DNA-PKcs S2056 phosphorylation and DSB recruitment. Alongside, ChIP-qPCR revealed GCN5 mediates transcription of PRKDC via H3K27Ac acetylation in its promoter region (- 710 to - 554). Genetic perturbation of GCN5 also decreased CHEK1, NBN1, TP53BP1, POL-L transcription and abrogated ATM, BRCA1 activation. Accordingly, GCN5 loss led to persistent ɣ-H2AX foci formation, compromised in-vivo HR-NHEJ and caused GBM radio-sensitization. Importantly, PARP1 inhibition phenocopied GCN5 loss. Together, this study identifies an untraversed DSB repair function of GCN5 and provides mechanistic insights into transcriptional as well as post-translational regulation of pivotal HR-NHEJ factors. Alongside, it highlights the translational importance of PARP1-GCN5 axis in mediating GBM radio-resistance.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"446"},"PeriodicalIF":5.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11544116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603168","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}

引用次数: 0

Ythdf2 facilitates precursor miR-378/miR-378-5p maturation to support myogenic differentiation. Ythdf2促进前体miR-378/miR-378-5p的成熟，以支持成肌分化。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-11-06 DOI: 10.1007/s00018-024-05456-0

Kaiping Deng, Yalong Su, Zhipeng Liu, Silu Hu, Caifang Ren, Wurilege Wei, Yixuan Fan, Yanli Zhang, Feng Wang

{"title":"Ythdf2 facilitates precursor miR-378/miR-378-5p maturation to support myogenic differentiation.","authors":"Kaiping Deng, Yalong Su, Zhipeng Liu, Silu Hu, Caifang Ren, Wurilege Wei, Yixuan Fan, Yanli Zhang, Feng Wang","doi":"10.1007/s00018-024-05456-0","DOIUrl":"10.1007/s00018-024-05456-0","url":null,"abstract":"Ythdf2 is known to mediate mRNA degradation in an m6A-dependent manner, and it has been shown to play a role in skeletal muscle differentiation. Recently, Ythdf2 was also found to bind to m6A-modified precursor miRNAs and regulate their maturation. However, it remains unknown whether this mechanism is related to the regulation of myogenesis by Ythdf2. Here, we observed that Ythdf2 knockdown significantly suppressed myotube formation and impacted miRNAs expression during myogenic differentiation. Through integrated analysis of miRNA and mRNA sequencing data, miR-378 and miR-378-5p were identified as important targets of Ythdf2 in myogenesis. Mechanically, Ythdf2 was found to interact with core components of the pre-miRNA processor complex, namely DICER1 and TARBP2, thereby facilitating the maturation of pre-miR-378/miR-378-5p in an m6A-dependent manner and resulting in an increase in the expression levels of mature miR-378 and miR-378-5p. Moreover, the downregulation of either miR-378 or miR-378-5p significantly inhibited myotube formation, while the forced expression of miR-378 or miR-378-5p could partially rescued Ythdf2 knockdown-induced suppression of myogenic differentiation by activating the mTOR pathway. Collectively, our results for the first time suggest that Ythdf2 regulates myogenic differentiation via mediating pre-miR-378/miR-378-5p maturation, which might provide new insights into the molecular mechanisms underlying m6A modification in the regulation of myogenesis.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"445"},"PeriodicalIF":6.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11541164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582408","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}

引用次数: 0

Transcriptomic alterations in APP/PS1 mice astrocytes lead to early postnatal axon initial segment structural changes. APP/PS1小鼠星形胶质细胞转录组的改变导致了出生后早期轴突初段结构的改变。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-11-01 DOI: 10.1007/s00018-024-05485-9

María José Benitez, Diana Retana, Lara Ordoñez-Gutiérrez, Inés Colmena, María José Goméz, Rebeca Álvarez, María Ciorraga, Ana Dopazo, Francisco Wandosell, Juan José Garrido

{"title":"Transcriptomic alterations in APP/PS1 mice astrocytes lead to early postnatal axon initial segment structural changes.","authors":"María José Benitez, Diana Retana, Lara Ordoñez-Gutiérrez, Inés Colmena, María José Goméz, Rebeca Álvarez, María Ciorraga, Ana Dopazo, Francisco Wandosell, Juan José Garrido","doi":"10.1007/s00018-024-05485-9","DOIUrl":"10.1007/s00018-024-05485-9","url":null,"abstract":"Alzheimer´s disease (AD) is characterized by neuronal function loss and degeneration. The integrity of the axon initial segment (AIS) is essential to maintain neuronal function and output. AIS alterations are detected in human post-mortem AD brains and mice models, as well as, neurodevelopmental and mental disorders. However, the mechanisms leading to AIS deregulation in AD and the extrinsic glial origin are elusive. We studied early postnatal differences in AIS cellular/molecular mechanisms in wild-type or APP/PS1 mice and combined neuron-astrocyte co-cultures. We observed AIS integrity alterations, reduced ankyrinG expression and shortening, in APP/PS1 mice from P21 and loss of AIS integrity at 21 DIV in wild-type and APP/PS1 neurons in the presence of APP/PS1 astrocytes. AnkyrinG decrease is due to mRNAs and protein reduction of retinoic acid synthesis enzymes Rdh1 and Aldh1b1, as well as ADNP (Activity-dependent neuroprotective protein) in APP/PS1 astrocytes. This effect was mimicked by wild-type astrocytes expressing ADNP shRNA. In the presence of APP/PS1 astrocytes, wild-type neurons AIS is recovered by inhibition of retinoic acid degradation, and Adnp-derived NAP peptide (NAPVSIPQ) addition or P2X7 receptor inhibition, both regulated by retinoic acid levels. Moreover, P2X7 inhibitor treatment for 2 months impaired AIS disruption in APP/PS1 mice. Our findings extend current knowledge on AIS regulation, providing data to support the role of astrocytes in early postnatal AIS modulation. In conclusion, AD onset may be related to very early glial cell alterations that induce AIS and neuronal function changes, opening new therapeutic approaches to detect and avoid neuronal function loss.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"444"},"PeriodicalIF":6.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562671","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}

引用次数: 0

The interplay of gut microbiota, obesity, and depression: insights and interventions. 肠道微生物群、肥胖症和抑郁症的相互作用：见解和干预措施。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-10-30 DOI: 10.1007/s00018-024-05476-w

Iryna Halabitska, Pavlo Petakh, Iryna Kamyshna, Valentyn Oksenych, Denis E Kainov, Oleksandr Kamyshnyi

引用次数: 0

Selective regulation of aspartyl intramembrane protease activity by calnexin. 萼片蛋白对天冬氨酰膜内蛋白酶活性的选择性调控

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-10-26 DOI: 10.1007/s00018-024-05478-8

Whendy Contreras, Jody Groenendyk, Marc Gentzel, Pascal Y Schönberg, Frank Buchholz, Marek Michalak, Bernd Schröder, Torben Mentrup

{"title":"Selective regulation of aspartyl intramembrane protease activity by calnexin.","authors":"Whendy Contreras, Jody Groenendyk, Marc Gentzel, Pascal Y Schönberg, Frank Buchholz, Marek Michalak, Bernd Schröder, Torben Mentrup","doi":"10.1007/s00018-024-05478-8","DOIUrl":"10.1007/s00018-024-05478-8","url":null,"abstract":"Signal peptide peptidase-like 2c (SPPL2c) is a testis-specific aspartyl intramembrane protease that contributes to male gamete function both by catalytic and non-proteolytic mechanisms. Here, we provide an unbiased characterisation of the in vivo interactome of SPPL2c identifying the ER chaperone calnexin as novel binding partner of this enzyme. Recruitment of calnexin specifically required the N-glycosylation within the N-terminal protease-associated domain of SPPL2c. Importantly, mutation of the single glycosylation site of SPPL2c or loss of calnexin expression completely prevented SPPL2c-mediated intramembrane proteolysis of all tested substrates. By contrast and despite rather promiscuous binding of calnexin to other SPP/SPPL proteases, expression of the chaperone was exclusively required for SPPL2c-mediated proteolysis. Despite some impact on the stability of SPPL2c most presumably due to assistance in folding of the luminal domain of the protease, calnexin appeared to be recruited rather constitutively to the protease thereby boosting its catalytic activity. In summary, we describe a novel, highly specific mode of intramembrane protease regulation, highlighting the need to systematically approach control mechanisms governing the proteolytic activity of other members of the aspartyl intramembrane protease family.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"441"},"PeriodicalIF":6.2,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496094","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}

引用次数: 0

The pluripotent-to-totipotent state transition in mESCs activates the intrinsic apoptotic pathway through DUX-induced DNA replication stress. mESC 中多能到全能状态的转变通过 DUX 诱导的 DNA 复制压力激活了内在凋亡途径。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-10-26 DOI: 10.1007/s00018-024-05465-z

Shunze Jia, Xinpeng Wen, Minwei Zhu, Xudong Fu

{"title":"The pluripotent-to-totipotent state transition in mESCs activates the intrinsic apoptotic pathway through DUX-induced DNA replication stress.","authors":"Shunze Jia, Xinpeng Wen, Minwei Zhu, Xudong Fu","doi":"10.1007/s00018-024-05465-z","DOIUrl":"10.1007/s00018-024-05465-z","url":null,"abstract":"The pluripotent mouse embryonic stem cell (mESCs) can transit into the totipotent-like state, and the transcription factor DUX is one of the master regulators of this transition. Intriguingly, this transition in mESCs is accompanied by massive cell death, which significantly impedes the establishment and maintenance of totipotent cells in vitro, yet the underlying mechanisms of this cell death remain largely elusive. In this study, we found that the totipotency transition in mESCs triggered cell death through the upregulation of DUX. Specifically, R-loops are accumulated upon DUX induction, which subsequently lead to DNA replication stress (RS) in mESCs. This RS further activates p53 and PMAIP1, ultimately leading to Caspase-9/7-dependent intrinsic apoptosis. Notably, inhibiting this intrinsic apoptosis not only mitigates cell death but also enhances the efficiency of the totipotency transition in mESCs. Our findings thus elucidate one of the mechanisms underlying cell apoptosis during the totipotency transition in mESCs and provide a strategy for optimizing the establishment and maintenance of totipotent cells in vitro.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"440"},"PeriodicalIF":6.2,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496097","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}

引用次数: 0