Annemarie Schwab, Mohammad Aarif Siddiqui, Vignesh Ramesh, Paradesi Naidu Gollavilli, Adriana Martinez Turtos, Sarah Søgaard Møller, Luisa Pinna, Jesper F. Havelund, Anne Mette A. Rømer, Pelin Gülizar Ersan, Beatrice Parma, Sabine Marschall, Katja Dettmer, Mohammed Alhusayan, Pietro Bertoglio, Giulia Querzoli, Dirk Mielenz, Ozgur Sahin, Nils J. Færgeman, Irfan A. Asangani, Paolo Ceppi
{"title":"Polyol pathway-generated fructose is indispensable for growth and survival of non-small cell lung cancer","authors":"Annemarie Schwab, Mohammad Aarif Siddiqui, Vignesh Ramesh, Paradesi Naidu Gollavilli, Adriana Martinez Turtos, Sarah Søgaard Møller, Luisa Pinna, Jesper F. Havelund, Anne Mette A. Rømer, Pelin Gülizar Ersan, Beatrice Parma, Sabine Marschall, Katja Dettmer, Mohammed Alhusayan, Pietro Bertoglio, Giulia Querzoli, Dirk Mielenz, Ozgur Sahin, Nils J. Færgeman, Irfan A. Asangani, Paolo Ceppi","doi":"10.1038/s41418-024-01415-1","DOIUrl":"https://doi.org/10.1038/s41418-024-01415-1","url":null,"abstract":"<p>Despite recent treatment advances, non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related deaths worldwide, and therefore it necessitates the exploration of new therapy options. One commonly shared feature of malignant cells is their ability to hijack metabolic pathways to confer survival or proliferation. In this study, we highlight the importance of the polyol pathway (PP) in NSCLC metabolism. This pathway is solely responsible for metabolizing glucose to fructose based on the enzymatic activity of aldose reductase (AKR1B1) and sorbitol dehydrogenase (SORD). Via genetic and pharmacological manipulations, we reveal that PP activity is indispensable for NSCLC growth and survival in vitro and in murine xenograft models. Mechanistically, PP deficiency provokes multifactorial deficits, ranging from energetic breakdown and DNA damage, that ultimately trigger the induction of apoptosis. At the molecular level, this process is driven by pro-apoptotic JNK signaling and concomitant upregulation of the transcription factors c-Jun and ATF3. Moreover, we show that fructose, the PP end-product, as well as other non-glycolytic hexoses confer survival to cancer cells and resistance against chemotherapy via sustained NF-κB activity as well as an oxidative switch in metabolism. Given the detrimental consequence of PP gene targeting on growth and survival, we propose PP pathway interference as a viable therapeutic approach against NSCLC.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"65 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673936","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}
{"title":"KBTBD2 controls bone development by regulating IGF-1 signaling during osteoblast differentiation","authors":"Yu Xun, Yiao Jiang, Aysha Khalid, Zeru Tian, Jonathan Rios, Zhao Zhang","doi":"10.1038/s41418-024-01416-0","DOIUrl":"https://doi.org/10.1038/s41418-024-01416-0","url":null,"abstract":"<p>Kelch repeat and BTB (POZ) domain-containing 2 (KBTBD2) is known for its pivotal role in metabolic regulation, particularly in adipocytes. However, its significance in skeletal development has remained elusive. Here, we uncover a previously unrecognized function of KBTBD2 in bone formation. Conditional knockout of <i>Kbtbd2</i> in embryonic osteochondroprogenitor cells or osteoblasts results in impaired osteogenic differentiation, leading to reduced skeletal growth and mineralization. Mechanistically, the loss of KBTBD2 during osteogenesis leads to the accumulation of p85α, a regulatory subunit encoded by <i>phosphoinositide-3-kinase regulatory subunit 1</i> (<i>Pik3r1</i>), which exerts a potent inhibitory effect on insulin-like growth factor 1 (IGF-1)-induced activation of AKT. Moreover, our study extends the understanding of KBTBD2’s relevance beyond bone biology to the context of SHORT syndrome, a rare genetic disorder marked by short stature and various physical abnormalities. We demonstrate that p85α harboring the p.(Arg649Trp) mutation, most frequently found in SHORT syndrome patients, exhibits reduced binding to KBTBD2, leading to impaired IGF-1-mediated activation of AKT. These findings reveal that KBTBD2 is essential in bone formation via regulating the IGF-1 signaling pathway and suggest loss of KBTBD2-mediated regulation of p85α as a potential mechanism for SHORT syndrome.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"46 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673938","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}
{"title":"ACBP/DBI neutralization for the experimental treatment of fatty liver disease.","authors":"Omar Motiño, Flavia Lambertucci, Adrien Joseph, Sylvère Durand, Gerasimos Anagnostopoulos, Sijing Li, Vincent Carbonnier, Uxía Nogueira-Recalde, Léa Montégut, Hui Chen, Fanny Aprahamian, Nitharsshini Nirmalathasan, Maria Chiara Maiuri, Federico Pietrocola, Dominique Valla, Cédric Laouénan, Jean-François Gautier, Laurent Castera, Isabelle Martins, Guido Kroemer","doi":"10.1038/s41418-024-01410-6","DOIUrl":"https://doi.org/10.1038/s41418-024-01410-6","url":null,"abstract":"<p><p>Acyl-CoA binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular checkpoint of autophagy. Here, we report that patients with histologically confirmed metabolic-associated steatohepatitis (MASH) or liver fibrosis exhibit elevated levels of circulating ACBP/DBI protein as compared to non-affected controls. Plasma ACBP/DBI strongly correlated with the NAFLD and FIB4 scores in patients, and these correlations were independent of age and body mass index. We studied the capacity of a monoclonal antibody (mAb) neutralizing mouse ACBP/DBI to combat active liver disease in several mouse models, in which steatohepatitis had been induced by four different protocols, namely, (i) methionine/choline-deficient diet, (ii) Western style diet (WD) alone, (iii) WD combined with the hepatotoxic agent CCl<sub>4</sub>, and (iv) a combination of CCl<sub>4</sub> injections and oral ethanol challenge. Injections of anti-ACBP/DBI mAb attenuated histological, enzymological, metabolomic and transcriptomic signs of liver damage in these four models, hence halting or reducing the progression of non-alcoholic and alcoholic liver disease. Steatosis, inflammation, ballooning and fibrosis responded to ACBP/DBI inhibition at the preclinical level. Altogether, these findings support a causal role of ACBP/DBI in MASH and liver fibrosis, as well as the possibility to therapeutically target ACBP/DBI.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643750","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}
Hao Liu, Shanliang Zheng, Guixue Hou, Junren Dai, Yanan Zhao, Fan Yang, Zhiyuan Xiang, Wenxin Zhang, Xingwen Wang, Yafan Gong, Li Li, Ning Zhang, Ying Hu
{"title":"AKAP1/PKA-mediated GRP75 phosphorylation at mitochondria-associated endoplasmic reticulum membranes protects cancer cells against ferroptosis","authors":"Hao Liu, Shanliang Zheng, Guixue Hou, Junren Dai, Yanan Zhao, Fan Yang, Zhiyuan Xiang, Wenxin Zhang, Xingwen Wang, Yafan Gong, Li Li, Ning Zhang, Ying Hu","doi":"10.1038/s41418-024-01414-2","DOIUrl":"https://doi.org/10.1038/s41418-024-01414-2","url":null,"abstract":"<p>Emerging evidence suggests that signaling pathways can be spatially regulated to ensure rapid and efficient responses to dynamically changing local cues. Ferroptosis is a recently defined form of lipid peroxidation-driven cell death. Although the molecular mechanisms underlying ferroptosis are emerging, spatial aspects of its signaling remain largely unexplored. By analyzing a public database, we found that a mitochondrial chaperone protein, glucose-regulated protein 75 (GRP75), may have a previously undefined role in regulating ferroptosis. This was subsequently validated. Interestingly, under ferroptotic conditions, GRP75 translocated from mitochondria to mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) and the cytosol. Further mechanistic studies revealed a highly spatial regulation of GRP75-mediated antiferroptotic signaling. Under ferroptotic conditions, lipid peroxidation predominantly accumulated at the ER, which activated protein kinase A (PKA) in a cAMP-dependent manner. In particular, a signaling microdomain, the outer mitochondrial membrane protein A-kinase anchor protein 1 (AKAP1)-anchored PKA, phosphorylated GRP75 at S148 in MAMs. This caused GRP75 to be sequestered outside the mitochondria, where it competed with Nrf2 for Keap1 binding through a conserved high-affinity RGD-binding motif, ETGE. Nrf2 was then stabilized and activated, leading to the transcriptional activation of a panel of antiferroptotic genes. Blockade of the PKA/GRP75 axis dramatically increased the responses of cancer cells to ferroptosis both in vivo and in vitro. Our identification a localized signaling cascade involved in protecting cancer cells from ferroptosis broadens our understanding of cellular defense mechanisms against ferroptosis and also provides a new target axis (AKAP1/PKA/GRP75) to improve the responses of cancer cells to ferroptosis.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"56 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610142","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}
Consuelo Pitolli, Alberto Marini, Claudio Sette, Vittoria Pagliarini
{"title":"Physiological and pathological roles of the transcriptional kinases CDK12 and CDK13 in the central nervous system","authors":"Consuelo Pitolli, Alberto Marini, Claudio Sette, Vittoria Pagliarini","doi":"10.1038/s41418-024-01413-3","DOIUrl":"https://doi.org/10.1038/s41418-024-01413-3","url":null,"abstract":"<p>The cyclin-dependent kinases 12 (CDK12) and 13 (CDK13) govern several steps of gene expression, including transcription, RNA processing and translation. The main target of CDK12/13 is the serine 2 residue of the carboxy-terminal domain of RNA polymerase II (RNAPII), thus influencing the directionality, elongation rate and processivity of the enzyme. The CDK12/13-dependent regulation of RNAPII activity influences the expression of selected target genes with important functional roles in the proliferation and viability of all eukaryotic cells. Neuronal cells are particularly affected by the loss of CDK12/13, as result of the high dependency of neuronal genes on RNAPII processivity for their expression. Deregulation of CDK12/13 activity strongly affects brain physiology by influencing the stemness potential and differentiation properties of neuronal precursor cells. Moreover, mounting evidence also suggest the involvement of CDK12/13 in brain tumours. Herein, we discuss the functional role(s) of CDK12 and CDK13 in gene expression regulation and highlight similarities and differences between these highly homologous kinases, with particular attention to their impact on brain physiology and pathology. Lastly, we provide an overview of CDK12/13 inhibitors and of their efficacy in brain tumours and other neoplastic diseases.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"22 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142600989","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}
{"title":"Integrin β6/Annexin A2 axis triggers autophagy to orchestrate hepatocellular carcinoma radioresistance","authors":"Ying Gao, Guangyan Wei, Hua Yu, Shuping Li, Yuhao Tang, Xin Yue, Yong Chen, Meixiao Zhan, Jian Wu","doi":"10.1038/s41418-024-01411-5","DOIUrl":"https://doi.org/10.1038/s41418-024-01411-5","url":null,"abstract":"<p>Radiotherapy (RT) is one of the main therapies for hepatocellular carcinoma (HCC), but its effectiveness has been constrained due to the resistance effect of radiation. Thus, the factors involved in radioresistance are evaluated and the underlying molecular mechanisms are also done. In this present study, we identified Integrin β6 (ITGB6) as a potential radioresistant gene through an integrative analysis of transcriptomic profiles, proteome datasets and survival using HCC cases treated with IR. We show that ITGB6 functionally contributed to radioresistance by activating autophagy through a series of in vitro and in vivo methods, such as clonogenic assays, autophagy flux (LC3B-GFP-mCherry reporter) analysis and a subcutaneous transplantation model. Mechanically, ITGB6 binds to Annexin A2 (ANXA2) and enhanced its stability by competitively antagonizing proteasome mediated ANXA2 degradation, thereby promoting autophagy and radioresistance. Notably, HCC radioresistance was significantly improved by either blocking ITGB6 or autophagy, but the combination was more effective. Importantly, ITGB6/ANXA2 axis triggered autophagic program endowed HCC cells with radioresistant activity in a radiated patient-derived xenograft (PDX) model and hydrodynamic injection in liver-specific <i>Itgb6</i>-knockout mice, further supported by clinical evidence. Together, our data revealed that ITGB6 is a radioresistant gene stabilizing the autophagy regulatory protein ANXA2, providing insights into the biological and potentially clinical significance of ITGB6/ANXA2 axis in radiotherapy planning of HCC.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"95 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601485","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}
{"title":"hnRNPA2B1 deacetylation by SIRT6 restrains local transcription and safeguards genome stability","authors":"Feng Chen, Wenchao Xu, Ming Tang, Yuan Tian, Yuxin Shu, Xingkai He, Linmin Zhou, Qi Liu, Qian Zhu, Xiaopeng Lu, Jun Zhang, Wei-Guo Zhu","doi":"10.1038/s41418-024-01412-4","DOIUrl":"https://doi.org/10.1038/s41418-024-01412-4","url":null,"abstract":"<p>Repair of double strand breaks (DSBs) by RNA-binding proteins (RBPs) is vital for ensuring genome integrity. DSB repair is accompanied by local transcriptional repression in the vicinity of transcriptionally active genes, but the mechanism by which RBPs regulate transcriptional regulation is unclear. Here, we demonstrated that RBP hnRNPA2B1 functions as a RNA polymerase-associated factor that stabilizes the transcription complex under physiological conditions. Following a DSB, hnRNPA2B1 is released from damaged chromatin, reducing the efficiency of RNAPII complex assembly, leading to local transcriptional repression. Mechanistically, SIRT6 deacetylates hnRNPA2B1 at K113/173 residues, enforcing its rapid detachment from DSBs. This process disrupts the integrity of the RNAPII complex on active chromatin, which is a pre-requisite for transient but complete repression of local transcription. Functionally, the overexpression of an acetylation mimic stabilizes the transcription complex and facilitates the functioning of the transcription machinery. hnRNPA2B1 acetylation status was negatively correlated with SIRT6 expression, and acetylation mimic enhanced radio-sensitivity in vivo. Our findings demonstrate that hnRNPA2B1 is crucial for transcriptional repression. We have uncovered the missing link between DSB repair and transcriptional regulation in genome stability maintenance, highlighting the potential of hnRNPA2B1 as a therapeutic target.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"13 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596851","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}
Holly Anderton, Esther Bandala-Sanchez, Daniel S Simpson, James A Rickard, Ashley P Ng, Ladina Di Rago, Cathrine Hall, James E Vince, John Silke, Gianmaria Liccardi, Rebecca Feltham
{"title":"Correction to: RIPK1 prevents TRADD-driven, but TNFR1 independent, apoptosis during development.","authors":"Holly Anderton, Esther Bandala-Sanchez, Daniel S Simpson, James A Rickard, Ashley P Ng, Ladina Di Rago, Cathrine Hall, James E Vince, John Silke, Gianmaria Liccardi, Rebecca Feltham","doi":"10.1038/s41418-024-01401-7","DOIUrl":"https://doi.org/10.1038/s41418-024-01401-7","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602898","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}
Jinkai Zhang, Hiu-Lam Rachel Kwan, Chi Bun Chan, Chi Wai Lee
{"title":"Localized release of muscle-generated BDNF regulates the initial formation of postsynaptic apparatus at neuromuscular synapses","authors":"Jinkai Zhang, Hiu-Lam Rachel Kwan, Chi Bun Chan, Chi Wai Lee","doi":"10.1038/s41418-024-01404-4","DOIUrl":"https://doi.org/10.1038/s41418-024-01404-4","url":null,"abstract":"<p>Growing evidence indicates that brain-derived neurotrophic factor (BDNF) is produced in contracting skeletal muscles and is secreted as a myokine that plays an important role in muscle metabolism. However, the involvement of muscle-generated BDNF and the regulation of its vesicular trafficking, localization, proteolytic processing, and spatially restricted release during the development of vertebrate neuromuscular junctions (NMJs) remain largely unknown. In this study, we first reported that BDNF is spatially associated with the actin-rich core domain of podosome-like structures (PLSs) at topologically complex acetylcholine receptor (AChR) clusters in cultured <i>Xenopus</i> muscle cells. The release of spatially localized BDNF is tightly controlled by activity-regulated mechanisms in a calcium-dependent manner. Live-cell time-lapse imaging further showed that BDNF-containing vesicles are transported to and captured at PLSs in both aneural and synaptic AChR clusters for spatially restricted release. Functionally, BDNF knockdown or furin-mediated endoproteolytic activity inhibition significantly suppresses aneural AChR cluster formation, which in turn affects synaptic AChR clustering induced by nerve innervation or agrin-coated beads. Lastly, skeletal muscle-specific BDNF knockout (MBKO) mice exhibit structural defects in the formation of aneural AChR clusters and their subsequent recruitment to nerve-induced synaptic AChR clusters during the initial stages of NMJ development in vivo. Together, this study demonstrated the regulatory roles of PLSs in the intracellular trafficking, spatial localization, and activity-dependent release of BDNF in muscle cells and revealed the involvement of muscle-generated BDNF and its proteolytic conversion in regulating the initial formation of aneural and synaptic AChR clusters during early NMJ development in vitro and in vivo.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"18 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594713","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}