Cellular and Molecular Life Sciences最新文献

Regulation of yeast polarized exocytosis by phosphoinositide lipids. 磷脂对酵母极化外吞的调控

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-11-19 DOI: 10.1007/s00018-024-05483-x

Matthew W Volpiana, Aleksa Nenadic, Christopher T Beh

{"title":"Regulation of yeast polarized exocytosis by phosphoinositide lipids.","authors":"Matthew W Volpiana, Aleksa Nenadic, Christopher T Beh","doi":"10.1007/s00018-024-05483-x","DOIUrl":"https://doi.org/10.1007/s00018-024-05483-x","url":null,"abstract":"Phosphoinositides help steer membrane trafficking routes within eukaryotic cells. In polarized exocytosis, which targets vesicular cargo to sites of polarized growth at the plasma membrane (PM), the two phosphoinositides phosphatidylinositol 4-phosphate (PI4P) and its derivative phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) pave the pathway for vesicle transport from the Golgi to the PM. PI4P is a critical regulator of mechanisms that shape late Golgi membranes for vesicle biogenesis and release. Although enriched in vesicle membranes, PI4P is inexplicably removed from post-Golgi vesicles during their transit to the PM, which drives subsequent steps in exocytosis. At the PM, PI(4,5)P2 recruits effectors that establish polarized membrane sites for targeting the vesicular delivery of secretory cargo. The budding yeast Saccharomyces cerevisiae provides an elegant model to unravel the complexities of phosphoinositide regulation during polarized exocytosis. Here, we review how PI4P and PI(4,5)P2 promote yeast vesicle biogenesis, exocyst complex assembly and vesicle docking at polarized cortical sites, and suggest how these steps might impact related mechanisms of human disease.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"457"},"PeriodicalIF":6.2,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667273","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

NFκB and JNK pathways mediate metabolic adaptation upon ESCRT-I deficiency. NFκB 和 JNK 通路在 ESCRT-I 缺乏时介导代谢适应。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-11-19 DOI: 10.1007/s00018-024-05490-y

Jaroslaw Cendrowski, Marta Wrobel, Michal Mazur, Bartosz Jary, Ranjana Maurya, Surui Wang, Michal Korostynski, Anna Dziewulska, Maria Rohm, Patryk Kuropka, Natalia Pudelko-Malik, Piotr Mlynarz, Agnieszka Dobrzyn, Anja Zeigerer, Marta Miaczynska

{"title":"NFκB and JNK pathways mediate metabolic adaptation upon ESCRT-I deficiency.","authors":"Jaroslaw Cendrowski, Marta Wrobel, Michal Mazur, Bartosz Jary, Ranjana Maurya, Surui Wang, Michal Korostynski, Anna Dziewulska, Maria Rohm, Patryk Kuropka, Natalia Pudelko-Malik, Piotr Mlynarz, Agnieszka Dobrzyn, Anja Zeigerer, Marta Miaczynska","doi":"10.1007/s00018-024-05490-y","DOIUrl":"https://doi.org/10.1007/s00018-024-05490-y","url":null,"abstract":"Endosomal Sorting Complexes Required for Transport (ESCRTs) are crucial for delivering membrane receptors or intracellular organelles for lysosomal degradation which provides the cell with lysosome-derived nutrients. Yet, how ESCRT dysfunction affects cell metabolism remained elusive. To address this, we analyzed transcriptomes of cells lacking TSG101 or VPS28 proteins, components of ESCRT-I subcomplex. ESCRT-I deficiency reduced the expression of genes encoding enzymes involved in oxidation of fatty acids and amino acids, such as branched-chain amino acids, and increased the expression of genes encoding glycolytic enzymes. The changes in metabolic gene expression were associated with Warburg effect-like metabolic reprogramming that included intracellular accumulation of lipids, increased glucose/glutamine consumption and lactate production. Moreover, depletion of ESCRT-I components led to expansion of the ER and accumulation of small mitochondria, most of which retained proper potential and performed ATP-linked respiration. Mechanistically, the observed transcriptional reprogramming towards glycolysis in the absence of ESCRT-I occurred due to activation of the canonical NFκB and JNK signaling pathways and at least in part by perturbed lysosomal degradation. We propose that by activating the stress signaling pathways ESCRT-I deficiency leads to preferential usage of extracellular nutrients, like glucose and glutamine, for energy production instead of lysosome-derived nutrients, such as fatty acids and branched-chain amino acids.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"458"},"PeriodicalIF":6.2,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667222","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

rTM reprograms macrophages via the HIF-1α/METTL3/PFKM axis to protect mice against sepsis. rTM 通过 HIF-1α/METTL3/PFKM 轴对巨噬细胞进行重编程，保护小鼠免受败血症的侵害。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-11-16 DOI: 10.1007/s00018-024-05489-5

Chen Yao, Hanyong Zhu, Binbin Ji, Hui Guo, Zimeng Liu, Ni Yang, Qi Zhang, Kangning Hai, Chenbo Gao, Jie Zhao, Xueqin Li, Rongqing Li, Xin Chen, Fandong Meng, Xiucheng Pan, Chunling Fu, Wanpeng Cheng, Fuxing Dong, Jing Yang, Yuchen Pan, Takayuki Ikezoe

{"title":"rTM reprograms macrophages via the HIF-1α/METTL3/PFKM axis to protect mice against sepsis.","authors":"Chen Yao, Hanyong Zhu, Binbin Ji, Hui Guo, Zimeng Liu, Ni Yang, Qi Zhang, Kangning Hai, Chenbo Gao, Jie Zhao, Xueqin Li, Rongqing Li, Xin Chen, Fandong Meng, Xiucheng Pan, Chunling Fu, Wanpeng Cheng, Fuxing Dong, Jing Yang, Yuchen Pan, Takayuki Ikezoe","doi":"10.1007/s00018-024-05489-5","DOIUrl":"10.1007/s00018-024-05489-5","url":null,"abstract":"The metabolic reprogramming of macrophages is a potential therapeutic strategy for sepsis treatment, but the mechanism underlying this reprogramming remains unclear. Since glycolysis can drive macrophage phenotype switching, the rate-limiting enzymes in glycolysis may be key to treating sepsis. Here, we found that, compared with other isoenzymes, the expression of 6-phosphofructokinase, muscle type (PFKM) was the most upregulated in monocytes from septic patients. Recombinant thrombomodulin (rTM) treatment downregulated the protein expression of PFKM in macrophages. Both rTM treatment and Pfkm knockout protected mice from sepsis and reduced the production of the proinflammatory cytokines IL-1β, IL-6, TNF-α, and IL-27, whereas PFKM overexpression increased the production of these cytokines. Mechanistically, rTM treatment inhibited glycolysis in macrophages by decreasing PFKM expression in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. HIF-1α overexpression increased methyltransferase-like 3 (METTL3) expression, elevated the m6A level on Pfkm, and upregulated the protein expression of PFKM. METTL3 silence attenuated HIF-1α-mediated PFKM expression. These findings provide insight into the underlying mechanism of macrophage reprogramming for the treatment of sepsis.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"456"},"PeriodicalIF":6.2,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11569104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643870","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

Correction: Tyrosine kinase 2 modulates splenic B cells through type I IFN and TLR7 signaling. 更正：酪氨酸激酶 2 通过 I 型 IFN 和 TLR7 信号调节脾脏 B 细胞。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-11-15 DOI: 10.1007/s00018-024-05482-y

Irene Bodega-Mayor, Pablo Delgado-Wicke, Alejandro Arrabal, Estíbaliz Alegría-Carrasco, Ana Nicolao-Gómez, Marta Jaén-Castaño, Cristina Espadas, Ana Dopazo, Enrique Martín-Gayo, María Luisa Gaspar, Belén de Andrés, Elena Fernández-Ruiz

引用次数: 0

αKlotho modulates BNIP3-mediated mitophagy by regulating FoxO3 to decrease mitochondrial ROS and apoptosis in contrast-induced acute kidney injury. 在对比剂诱导的急性肾损伤中，αKlotho通过调节FoxO3来减少线粒体ROS和细胞凋亡，从而调节BNIP3介导的有丝分裂。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-11-15 DOI: 10.1007/s00018-024-05473-z

Xuying Zhu, Qisheng Lin, Yuanting Yang, Shu Li, Xinghua Shao, Weiming Zhang, Hong Cai, Jialin Li, Jingkui Wu, Kaiqi Zhang, Chaojun Qi, Minfang Zhang, Xiajing Che, Leyi Gu, Zhaohui Ni

{"title":"αKlotho modulates BNIP3-mediated mitophagy by regulating FoxO3 to decrease mitochondrial ROS and apoptosis in contrast-induced acute kidney injury.","authors":"Xuying Zhu, Qisheng Lin, Yuanting Yang, Shu Li, Xinghua Shao, Weiming Zhang, Hong Cai, Jialin Li, Jingkui Wu, Kaiqi Zhang, Chaojun Qi, Minfang Zhang, Xiajing Che, Leyi Gu, Zhaohui Ni","doi":"10.1007/s00018-024-05473-z","DOIUrl":"10.1007/s00018-024-05473-z","url":null,"abstract":"Contrast-induced acute kidney injury (CI-AKI) is one of the main causes of hospital-acquired renal failure, and still lacks of effective treatments. Previously, we demonstrated that αKlotho, which is an anti-aging protein that highly expresses in the kidney, has therapeutic activity in CI-AKI through promoting autophagy. However, the specific mechanism underlying αKlotho-mediated autophagy remains unclear. The RNA sequencing analysis of renal cortex revealed that the differentially expressed genes related to autophagy between αKlotho-treated CI-AKI mice and vehicle-treated CI-AKI mice were found to be associated with mitophagy and apoptosis. In the kidney of CI-AKI mice and HK-2 cells exposed to Iohexol, we revealed that αKlotho promoted mitophagy and decreased cell apoptosis. Mechanistically, αKlotho attenuated mitochondria damage, decreased mitochondrial ROS by upregulating BNIP3-mediated mitophagy. BNIP3 deletion abolished the beneficial effects of αKlotho both in vivo and in vitro. Moreover, we further demonstrated that αKlotho upregulated FoxO3 nuclear expression in Iohexol-treated HK-2 cells. Knockdown of FOXO3 gene inhibited αKlotho-promoted BNIP3-mediated mitophagy and subsequently increased the oxidative injury and cell apoptosis. Taken together, our results indicated a critical role of αKlotho in alleviating CI-AKI via mitophagy promotion involving the FoxO3-BNIP3 pathway.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"454"},"PeriodicalIF":6.2,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638522","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

Helicobacter pylori promotes gastric cancer progression by activating the TGF-β/Smad2/EMT pathway through HKDC1. 幽门螺杆菌通过 HKDC1 激活 TGF-β/Smad2/EMT 通路，从而促进胃癌进展。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-11-15 DOI: 10.1007/s00018-024-05491-x

Ziqing Fang, Weitong Zhang, Huizhen Wang, Chaoyang Zhang, Jing Li, Wanjing Chen, Xin Xu, Luyang Wang, Mengdi Ma, Shangxin Zhang, Yongxiang Li

{"title":"Helicobacter pylori promotes gastric cancer progression by activating the TGF-β/Smad2/EMT pathway through HKDC1.","authors":"Ziqing Fang, Weitong Zhang, Huizhen Wang, Chaoyang Zhang, Jing Li, Wanjing Chen, Xin Xu, Luyang Wang, Mengdi Ma, Shangxin Zhang, Yongxiang Li","doi":"10.1007/s00018-024-05491-x","DOIUrl":"10.1007/s00018-024-05491-x","url":null,"abstract":"Helicobacter pylori (H. pylori) infection is widely acknowledged as the primary risk factor for gastric cancer, facilitating its progression via the Correa cascade. Concurrently, Hexokinase Domain Containing 1 (HKDC1) has been implicated in the mediation of aerobic glycolysis, contributing to tumorigenesis across various cancers. However, the precise role of HKDC1 in the inflammatory transformation associated with H. pylori-induced gastric cancer remains elusive. In this study, transcriptome sequencing revealed a significant correlation between HKDC1 and H. pylori-induced gastric cancer. Subsequent validation using qRT-PCR, immunohistochemistry, and Western blot analysis confirmed elevated HKDC1 expression in both human and murine gastritis and gastric tumors. Moreover, in vitro and in vivo experiments demonstrated that H. pylori infection up-regulates TGF-β1 and p-Smad2, thereby activating the epithelial-mesenchymal transition (EMT) pathway, with HKDC1 playing a pivotal role. Suppression of HKDC1 expression or pharmacological inhibition of TGF-β1 reversed EMT activation, consequently reducing gastric cancer cell proliferation and metastasis. These results underscore HKDC1's essential contribution to H. pylori-induced gastric cancer progression via EMT activation.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"453"},"PeriodicalIF":6.2,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638520","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

Neutrophil-centric analysis of gastric cancer: prognostic modeling and molecular insights. 以中性粒细胞为中心的胃癌分析：预后模型和分子洞察力。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-11-14 DOI: 10.1007/s00018-024-05484-w

Guangbo Tang, Qiong Song, Jianhua Dou, Zhangqian Chen, Xi Hu, Zihang Li, Xiujuan Li, Tingjie Wang, Shanshan Dong, Huqin Zhang

{"title":"Neutrophil-centric analysis of gastric cancer: prognostic modeling and molecular insights.","authors":"Guangbo Tang, Qiong Song, Jianhua Dou, Zhangqian Chen, Xi Hu, Zihang Li, Xiujuan Li, Tingjie Wang, Shanshan Dong, Huqin Zhang","doi":"10.1007/s00018-024-05484-w","DOIUrl":"10.1007/s00018-024-05484-w","url":null,"abstract":"Gastric cancer remains a significant global health concern with poor prognosis. This study investigates the role of neutrophils in gastric cancer progression and their potential as prognostic indicators. Using multi-omics approaches, including Weighted Gene Co-expression Network Analysis (WGCNA), machine learning, and single-cell analysis, we identified neutrophil-associated gene signatures and developed a robust prognostic model. Our findings reveal distinct gastric cancer subtypes based on neutrophil-associated genes, with one subtype showing increased neutrophil infiltration and poorer prognosis. Single-cell analysis uncovered neutrophil-associated alterations in cell composition, gene expression profiles, and intercellular communication within the tumor microenvironment. Additionally, we explored the relationship between neutrophil-associated genes, microbiota composition, and alternative splicing events in gastric cancer. Furthermore, we identified QKI as a key regulator of alternative splicing and demonstrated its role in promoting malignant phenotypes and enhancing TGF-beta signaling and epithelial-mesenchymal transition in gastric cancer cells by wet experiment. Lastly, the role of QKI in the association with drug resistance and the identification of specific agents for treating QKI-associated drug resistance were also explored. This comprehensive study provides novel insights into the complex interplay between neutrophils, the tumor microenvironment, microbiota, alternative splicing and gastric cancer progression, offering potential new targets for therapeutic intervention.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"452"},"PeriodicalIF":6.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616037","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

SPOP-mediated RIPK3 destabilization desensitizes LPS/sMAC/zVAD-induced necroptotic cell death. SPOP 介导的 RIPK3 失稳可使 LPS/sMAC/zVAD 诱导的坏死细胞死亡脱敏。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2024-11-14 DOI: 10.1007/s00018-024-05487-7

Ga-Eun Lee, Geul Bang, Jiin Byun, Weidong Chen, Dohyun Jeung, Hana Cho, Joo Young Lee, Han Chang Kang, Hye Suk Lee, Jin Young Kim, Kwang Dong Kim, Juan Wu, Soo-Bin Nam, Young Jik Kwon, Cheol-Jung Lee, Yong-Yeon Cho

{"title":"SPOP-mediated RIPK3 destabilization desensitizes LPS/sMAC/zVAD-induced necroptotic cell death.","authors":"Ga-Eun Lee, Geul Bang, Jiin Byun, Weidong Chen, Dohyun Jeung, Hana Cho, Joo Young Lee, Han Chang Kang, Hye Suk Lee, Jin Young Kim, Kwang Dong Kim, Juan Wu, Soo-Bin Nam, Young Jik Kwon, Cheol-Jung Lee, Yong-Yeon Cho","doi":"10.1007/s00018-024-05487-7","DOIUrl":"10.1007/s00018-024-05487-7","url":null,"abstract":"RIPK1/RIPK3-MLKL signaling molecules are fundamental in initiating necroptotic cell death, but their roles in the development of colon cancer are unclear. This study reports that RIPK3 interacted with SPOP, a component of the E3 ligase within the Cul3 complex. This interaction leads to K48-linked ubiquitination and subsequent proteasomal degradation of RIPK3. Two distinct degron motifs, PETST and SPTST, were identified within the linker domain of RIPK3 for SPOP. RIPK3 phosphorylations at Thr403 by PIM2 and at Thr412/Ser413 by ERK2 are essential to facilitate its interaction with SPOP. Computational docking studies and immunoprecipitation analyses showed that these PIM2 and ERK2 phosphorylations bolster the stability of the RIPK3-SPOP interaction. In particular, mutations of RIPK3 at the degron motifs extended the half-life of RIPK3 by preventing its phosphorylation and subsequent ubiquitination. The deletion of SPOP, which led to increased stability of the RIPK3 protein, intensified LPS/sMAC/zVAD-induced necroptotic cell death in colon cancer cells. These findings underscore the critical role of the SPOP-mediated RIPK3 stability regulation pathway in controlling necroptotic cell death.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"451"},"PeriodicalIF":6.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616038","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 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