Cell Death and Differentiation最新文献_第4页

Integrated stress response plasticity governs normal cell adaptation to chronic stress via the PP2A-TFE3-ATF4 pathway 综合应激反应可塑性通过 PP2A-TFE3-ATF4 通路调控正常细胞对慢性应激的适应性

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2024-09-30 DOI: 10.1038/s41418-024-01378-3

Rita A. Avelar, Riya Gupta, Grace Carvette, Felipe da Veiga Leprevost, Medhasri Jasti, Jose Colina, Jessica Teitel, Alexey I. Nesvizhskii, Caitlin M. O’Connor, Maria Hatzoglou, Shirish Shenolikar, Peter Arvan, Goutham Narla, Analisa DiFeo

{"title":"Integrated stress response plasticity governs normal cell adaptation to chronic stress via the PP2A-TFE3-ATF4 pathway","authors":"Rita A. Avelar, Riya Gupta, Grace Carvette, Felipe da Veiga Leprevost, Medhasri Jasti, Jose Colina, Jessica Teitel, Alexey I. Nesvizhskii, Caitlin M. O’Connor, Maria Hatzoglou, Shirish Shenolikar, Peter Arvan, Goutham Narla, Analisa DiFeo","doi":"10.1038/s41418-024-01378-3","DOIUrl":"https://doi.org/10.1038/s41418-024-01378-3","url":null,"abstract":"The integrated stress response (ISR) regulates cell fate during conditions of stress by leveraging the cell’s capacity to endure sustainable and efficient adaptive stress responses. Protein phosphatase 2A (PP2A) activity modulation has been shown to be successful in achieving both therapeutic efficacy and safety across various cancer models. However, the molecular mechanisms driving its selective antitumor effects remain unclear. Here, we show for the first time that ISR plasticity relies on PP2A activation to regulate drug response and dictate cellular survival under conditions of chronic stress. We demonstrate that genetic and chemical modulation of the PP2A leads to chronic proteolytic stress and triggers an ISR to dictate whether the cell lives or dies. More specifically, we uncovered that the PP2A-TFE3-ATF4 pathway governs ISR cell plasticity during endoplasmic reticular and cellular stress independent of the unfolded protein response. We further show that normal cells reprogram their genetic signatures to undergo ISR-mediated adaptation and homeostatic recovery thereby avoiding toxicity following PP2A-mediated stress. Conversely, oncogenic specific cytotoxicity induced by chemical modulation of PP2A is achieved by activating chronic and irreversible ISR in cancer cells. Our findings propose that a differential response to chemical modulation of PP2A is determined by intrinsic ISR plasticity, providing a novel biological vulnerability to selectively induce cancer cell death and improve targeted therapeutic efficacy.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"8 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Neuronal LAMP2A-mediated reduction of adenylyl cyclases induces acute neurodegenerative responses and neuroinflammation after ischemic stroke 神经元 LAMP2A 介导的腺苷酸环化酶减少诱导缺血性中风后的急性神经退行性反应和神经炎症

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2024-09-28 DOI: 10.1038/s41418-024-01389-0

Dingfang Shi, Yunhao Bai, Ruiling Long, Jing Xia, Wenxuan Xu, Dongshen Qin, Xuejun Yang, Ming Ding, Xiao-Yu Hou

{"title":"Neuronal LAMP2A-mediated reduction of adenylyl cyclases induces acute neurodegenerative responses and neuroinflammation after ischemic stroke","authors":"Dingfang Shi, Yunhao Bai, Ruiling Long, Jing Xia, Wenxuan Xu, Dongshen Qin, Xuejun Yang, Ming Ding, Xiao-Yu Hou","doi":"10.1038/s41418-024-01389-0","DOIUrl":"https://doi.org/10.1038/s41418-024-01389-0","url":null,"abstract":"Lysosomes regulate cellular metabolism to maintain cell survival, but the mechanisms whereby they determine neuronal cell fate after acute metabolic stress are unknown. Neuron-enriched lysosomal membrane protein LAMP2A is involved in selective chaperone-mediated autophagy and exosome loading. This study demonstrates that abnormalities in the neuronal LAMP2A-lysosomal pathway cause neurological deficits following ischemic stroke and that this is an early inducer of the PANoptosis-like molecular pathway and neuroinflammation, simultaneously inducing upregulation of FADD, RIPK3, and MLKL after ischemia. Quantitative proteomic and pharmacological analysis showed that after acute metabolic stress, the neuronal LAMP2A pathway induced acute synaptic degeneration and PANoptosis-like responses involving downregulation of protein kinase A (PKA) signaling. LAMP2A directed post-stroke lysosomal degradation of adenylyl cyclases (ADCY), including ADCY1 and ADCY3 in cortical neurons. Post-stroke treatment with cAMP mimetic or ADCY activator salvaged cortical neurons from PANoptosis-like responses and neuroinflammation, suggesting that the neuronal ADCY–cAMP–PKA axis is an upstream arrester of the pathophysiological process following an ischemic stroke. This study demonstrates that the neuronal LAMP2A-lysosmal pathway drives intricate acute neurodegenerative and neuroinflammatory responses after brain metabolic stress by downregulating the ADCY–PKA signaling cascade, and highlights the therapeutic potential of PKA signal inducers for improving stroke outcomes.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"42 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

NF-κB regulated expression of A20 controls IKK dependent repression of RIPK1 induced cell death in activated T cells 受 NF-κB 调控的 A20 表达可控制 IKK 依赖性抑制活化 T 细胞中 RIPK1 诱导的细胞死亡

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2024-09-26 DOI: 10.1038/s41418-024-01383-6

By Scott Layzell, Alessandro Barbarulo, Geert van Loo, Rudi Beyaert, Benedict Seddon

{"title":"NF-κB regulated expression of A20 controls IKK dependent repression of RIPK1 induced cell death in activated T cells","authors":"By Scott Layzell, Alessandro Barbarulo, Geert van Loo, Rudi Beyaert, Benedict Seddon","doi":"10.1038/s41418-024-01383-6","DOIUrl":"https://doi.org/10.1038/s41418-024-01383-6","url":null,"abstract":"IKK signalling is essential for survival of thymocytes by repressing RIPK1 induced cell death rather than its canonical function of activating NF-κB. The role of IKK signalling in activated T cells is unclear. To investigate this, we analysed activation of IKK2 deficient T cells. While TCR triggering was normal, proliferation and expansion was profoundly impaired. This was not due to defective cell cycle progression, rather dividing T cells became sensitised to TNF induced cell death, since inhibition of RIPK1 kinase activity rescued cell survival. Gene expression analysis of activated IKK2 deficient T cells revealed defective expression of Tnfaip3, that encodes A20, a negative regulator of NF-κB. To test whether A20 expression was required to protect IKK2 deficient T cells from cell death, we generated mice with T cells lacking both A20 and IKK2. Doing this resulted in near complete loss of peripheral T cells, in contrast to mice lacking one or other gene. Strikingly, this phenotype was completely reversed by inactivation of RIPK1 kinase activity in vivo. Together, our data show that IKK signalling in activated T cells protects against RIPK1 dependent death, both by direct phosphorylation of RIPK1 and through NF-κB mediated induction of A20, that we identify for the first time as a key modulator of RIPK1 activity in T cells.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"42 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

The role(s) of NF-Y in development and differentiation NF-Y 在发育和分化中的作用

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2024-09-26 DOI: 10.1038/s41418-024-01388-1

Diletta Dolfini, Carol Imbriano, Roberto Mantovani

引用次数: 0

Retraction Note: Hypoxia-induced autophagy of stellate cells inhibits expression and secretion of lumican into microenvironment of pancreatic ductal adenocarcinoma 撤稿说明：低氧诱导的星状细胞自噬抑制了胰腺导管腺癌微环境中lumican的表达和分泌。

IF 13.7 1区生物学

Cell Death and Differentiation Pub Date : 2024-09-25 DOI: 10.1038/s41418-024-01387-2

Xinqun Li, Yeonju Lee, Ya’an Kang, Bingbing Dai, Mayrim Rios Perez, Michael Pratt, Eugene J. Koay, Michael Kim, Rolf A. Brekken, Jason B. Fleming

引用次数: 0

ARHGAP26 deficiency drives the oocyte aneuploidy and early embryonic development failure. ARHGAP26 缺乏会导致卵母细胞非整倍体和早期胚胎发育失败。

IF 13.7 1区生物学

Cell Death and Differentiation Pub Date : 2024-09-23 DOI: 10.1038/s41418-024-01384-5

Sen Li, Yu Zhang, Ruiying Yuan, Shuai Zhu, Jie Bai, Yilong Miao, Xianghong Ou, Qiang Wang, Bo Xiong

{"title":"ARHGAP26 deficiency drives the oocyte aneuploidy and early embryonic development failure.","authors":"Sen Li, Yu Zhang, Ruiying Yuan, Shuai Zhu, Jie Bai, Yilong Miao, Xianghong Ou, Qiang Wang, Bo Xiong","doi":"10.1038/s41418-024-01384-5","DOIUrl":"10.1038/s41418-024-01384-5","url":null,"abstract":"Aneuploidy, the presence of a chromosomal anomaly, is a major cause of spontaneous abortions and recurrent pregnancy loss in humans. However, the underlying molecular mechanisms still remain poorly understood. Here, we report that ARHGAP26, a putative tumor suppressor gene, is a newly identified regulator of oocyte quality to maintain mitochondrial integrity and chromosome euploidy, thus ensuring normal embryonic development and fertility. Taking advantage of knockout mouse model, we revealed that genetic ablation of Arhgap26 caused the oocyte death at GV stage due to the mitochondrial dysfunction-induced ROS accumulation. Lack of Arhgap26 also impaired both in vitro and in vivo maturation of survived oocytes which results in maturation arrest and aneuploidy, and consequently leading to early embryonic development defects and subfertility. These observations were further verified by transcriptome analysis. Mechanistically, we discovered that Arhgap26 interacted with Cofilin1 to maintain the mitochondrial integrity by regulating Drp1 dynamics, and restoration of Arhgap26 protein level recovered the quality of Arhgap26-null oocytes. Importantly, we found an ARHGAP26 mutation in a patient with history of recurrent miscarriage by chromosomal microarray analysis. Altogether, our findings uncover a novel function of ARHGAP26 in the oocyte quality control and prevention of aneuploidy and provide a potential treatment strategy for infertile women caused by ARHGAP26 mutation.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

The IDH1-R132H mutation aggravates cisplatin-induced acute kidney injury by promoting ferroptosis through disrupting NDUFA1 and FSP1 interaction IDH1-R132H 突变通过破坏 NDUFA1 和 FSP1 的相互作用促进铁变态反应，从而加重顺铂诱导的急性肾损伤

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2024-09-22 DOI: 10.1038/s41418-024-01381-8

Kunmei Lai, Zhimin Chen, Siyi Lin, Keng Ye, Ying Yuan, Guoping Li, Yankun Song, Huabin Ma, Tak W. Mak, Yanfang Xu

{"title":"The IDH1-R132H mutation aggravates cisplatin-induced acute kidney injury by promoting ferroptosis through disrupting NDUFA1 and FSP1 interaction","authors":"Kunmei Lai, Zhimin Chen, Siyi Lin, Keng Ye, Ying Yuan, Guoping Li, Yankun Song, Huabin Ma, Tak W. Mak, Yanfang Xu","doi":"10.1038/s41418-024-01381-8","DOIUrl":"https://doi.org/10.1038/s41418-024-01381-8","url":null,"abstract":"The IDH1-R132H mutation is implicated in the development of various tumors. Whether cisplatin, a common chemotherapeutic agent, induces more significant renal toxicity in individuals with the IDH1-R132H mutation remains unclear. In this study, we observed that the IDH1-R132H mutation exacerbates mitochondrial lipid peroxidation and dysfunction in renal tubules, rendering the kidneys more susceptible to cisplatin-induced ferroptosis. The IDH1-R132H mutation increases methylation of the Ndufa1 promoter, thereby suppressing NDUFA1 transcription and translation. This suppression disrupts NDUFA1’s interaction with FSP1, reducing its resistance to cisplatin-induced tubular epithelial cell death. As a consequence, ROS accumulates, lipid peroxidation occurs, and ferroptosis is triggered, thereby promoting acute kidney injury. In summary, this study elucidates a novel mechanism underlying cisplatin-induced nephrotoxicity and provides valuable insights for the development of personalized treatment strategies for tumor patients carrying the IDH1-R132H mutation.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"25 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

The long non-coding RNA ROSALIND protects the mitochondrial translational machinery from oxidative damage 长非编码 RNA ROSALIND 保护线粒体翻译机制免受氧化损伤

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2024-09-18 DOI: 10.1038/s41418-024-01377-4

Vicky Katopodi, Alessandro Marino, Nikoleta Pateraki, Yvessa Verheyden, Sonia Cinque, Elena Lara Jimenez, Sara Adnane, Ewout Demesmaeker, Alice Scomparin, Rita Derua, Elisabetta Groaz, Eleonora Leucci

{"title":"The long non-coding RNA ROSALIND protects the mitochondrial translational machinery from oxidative damage","authors":"Vicky Katopodi, Alessandro Marino, Nikoleta Pateraki, Yvessa Verheyden, Sonia Cinque, Elena Lara Jimenez, Sara Adnane, Ewout Demesmaeker, Alice Scomparin, Rita Derua, Elisabetta Groaz, Eleonora Leucci","doi":"10.1038/s41418-024-01377-4","DOIUrl":"https://doi.org/10.1038/s41418-024-01377-4","url":null,"abstract":"Upregulation of mitochondrial respiration coupled with high ROS-scavenging capacity is a characteristic shared by drug-tolerant cells in several cancers. As translational fidelity is essential for cell fitness, protection of the mitochondrial and cytosolic ribosomes from oxidative damage is pivotal. While mechanisms for recognising and repairing such damage exist in the cytoplasm, the corresponding process in the mitochondria remains unclear.By performing Ascorbate PEroXidase (APEX)-proximity ligation assay directed to the mitochondrial matrix followed by isolation and sequencing of RNA associated to mitochondrial proteins, we identified the nuclear-encoded lncRNA ROSALIND as an interacting partner of ribosomes. ROSALIND is upregulated in recurrent tumours and its expression can discriminate between responders and non-responders to immune checkpoint blockade in a melanoma cohort of patients. Featuring an unusually high G content, ROSALIND serves as a substrate for oxidation. Consequently, inhibiting ROSALIND leads to an increase in ROS and protein oxidation, resulting in severe mitochondrial respiration defects. This, in turn, impairs melanoma cell viability and increases immunogenicity both in vitro and ex vivo in preclinical humanised cancer models. These findings underscore the role of ROSALIND as a novel ROS buffering system, safeguarding mitochondrial translation from oxidative stress, and shed light on potential therapeutic strategies for overcoming cancer therapy resistance.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"1 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Retention of ES cell-derived 129S genome drives NLRP1 hypersensitivity and transcriptional deregulation in Nlrp3tm1Flv mice 保留 ES 细胞衍生的 129S 基因组会导致 Nlrp3tm1Flv 小鼠 NLRP1 超敏和转录失调

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2024-09-17 DOI: 10.1038/s41418-024-01379-2

Felix D. Weiss, Yubell Alvarez, Farhad Shakeri, Anshupa Sahu, Petro Leka, Alesja Dernst, Jessika Rollheiser, Matilde Vasconcelos, Adriana Geraci, Fraser Duthie, Rainer Stahl, Hye Eun Lee, Anne-Kathrin Gellner, Andreas Buness, Eicke Latz, Felix Meissner

{"title":"Retention of ES cell-derived 129S genome drives NLRP1 hypersensitivity and transcriptional deregulation in Nlrp3tm1Flv mice","authors":"Felix D. Weiss, Yubell Alvarez, Farhad Shakeri, Anshupa Sahu, Petro Leka, Alesja Dernst, Jessika Rollheiser, Matilde Vasconcelos, Adriana Geraci, Fraser Duthie, Rainer Stahl, Hye Eun Lee, Anne-Kathrin Gellner, Andreas Buness, Eicke Latz, Felix Meissner","doi":"10.1038/s41418-024-01379-2","DOIUrl":"https://doi.org/10.1038/s41418-024-01379-2","url":null,"abstract":"Immune response genes are highly polymorphic in humans and mice, with heterogeneity amongst loci driving strain-specific host defence responses. The inadvertent retention of polymorphic loci can introduce confounding phenotypes, leading to erroneous conclusions, and impeding scientific advancement. In this study, we employ a combination of RNAseq and variant calling analyses to identify a substantial region of 129S genome, including the highly polymorphic Nlrp1 locus, proximal to Nlrp3, in one of the most commonly used mouse models of NLRP3 deficiency (Nlrp3tm1Flv). We show that the presence of the Nlrp1129S locus leads to an increase in NLRP1B protein expression, and a sensitising of Nlrp3tm1Flv macrophages to NLRP1 inflammasome activation, independent of NLRP3 deficiency. Retention of 129S genome further leads to protein sequence differences and altered gene regulation across multiple cell types, including of the key tissue-resident macrophage marker, TIM4. Using alternative models of NLRP3 deficiency, including a previously undescribed conditional Nlrp3 allele enabling precise temporal and cell-type specific control over Nlrp3 deletion, we further show that NLRP3 contributes to Talabostat-driven IL-1β release. Our study also establishes a generic framework to identify functionally relevant SNPs and assess genomic contamination in transgenic mice using RNAseq data. This allows for unambiguous attribution of phenotypes to the target gene and advances the precision and reliability of research in the field of host defence responses.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"4 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Feeding cancer to death - a triad of aromatic acids reduces tumor growth 喂死癌症--三重芳香酸可减少肿瘤生长

IF 13.7 1区生物学

Cell Death and Differentiation Pub Date : 2024-09-12 DOI: 10.1038/s41418-024-01372-9

Audrey Xavier, Ivan Dikic

引用次数: 0