Protein & CellPub Date : 2024-10-04DOI: 10.1093/procel/pwae055
Wenwen Wang, Pu Liu, Wendi Zhu, Tianwei Li, Ying Wang, Yujie Wang, Jun Li, Jie Ma, Ling Leng
{"title":"Skin organoid transplantation promotes tissue repair with scarless in frostbite.","authors":"Wenwen Wang, Pu Liu, Wendi Zhu, Tianwei Li, Ying Wang, Yujie Wang, Jun Li, Jie Ma, Ling Leng","doi":"10.1093/procel/pwae055","DOIUrl":"https://doi.org/10.1093/procel/pwae055","url":null,"abstract":"<p><p>Frostbite is the most common cold injury and is caused by both immediate cold-induced cell death and the gradual development of localized inflammation and tissue ischemia. Delayed healing of frostbite often leads to scar formation, which not only causes psychological distress but also tends to result in the development of secondary malignant tumors. Therefore, a rapid healing method for frostbite wounds is urgently needed. Herein, we used a mouse skin model of frostbite injury to evaluate the recovery process after frostbite. Moreover, single-cell transcriptomics was used to determine the patterns of changes in monocytes, macrophages, epidermal cells and fibroblasts during frostbite. Most importantly, human-induced pluripotent stem cell (hiPSC) -derived skin organoids combining with gelatin-hydrogel were constructed for the treatment of frostbite. The results showed that skin organoid treatment significantly accelerated wound healing by reducing early inflammation after frostbite and increasing the proportions of epidermal stem cells. Moreover, in the later stage of wound healing, skin organoids reduced the overall proportions of fibroblasts, significantly reduced fibroblast-to-myofibroblast transition by regulating the integrin α5β1-FAK pathway, and remodeled the extracellular matrix (ECM) through degradation and reassembly mechanisms, facilitating the restoration of physiological ECM and reducing the abundance of ECM associated with abnormal scar formation. These results highlight the potential application of organoids for promoting the reversal of frostbite-related injury and the recovery of skin functions. This study provides a new therapeutic alternative for patients suffering from disfigurement and skin dysfunction caused by frostbite.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372700","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}
Protein & CellPub Date : 2024-10-01DOI: 10.1093/procel/pwae015
Ding Ma, An Xie, Jiahui Lv, Xiaolin Min, Xinye Zhang, Qian Zhou, Daxing Gao, Enyu Wang, Lei Gao, Linzhao Cheng, Senquan Liu
{"title":"Engineered extracellular vesicles enable high-efficient delivery of intracellular therapeutic proteins.","authors":"Ding Ma, An Xie, Jiahui Lv, Xiaolin Min, Xinye Zhang, Qian Zhou, Daxing Gao, Enyu Wang, Lei Gao, Linzhao Cheng, Senquan Liu","doi":"10.1093/procel/pwae015","DOIUrl":"10.1093/procel/pwae015","url":null,"abstract":"<p><p>Developing an intracellular delivery system is of key importance in the expansion of protein-based therapeutics acting on cytosolic or nuclear targets. Recently, extracellular vesicles (EVs) have been exploited as next-generation delivery modalities due to their natural role in intercellular communication and biocompatibility. However, fusion of protein of interest to a scaffold represents a widely used strategy for cargo enrichment in EVs, which could compromise the stability and functionality of cargo. Herein, we report intracellular delivery via EV-based approach (IDEA) that efficiently packages and delivers native proteins both in vitro and in vivo without the use of a scaffold. As a proof-of-concept, we applied the IDEA to deliver cyclic GMP-AMP synthase (cGAS), an innate immune sensor. The results showed that cGAS-carrying EVs activated interferon signaling and elicited enhanced antitumor immunity in multiple syngeneic tumor models. Combining cGAS EVs with immune checkpoint inhibition further synergistically boosted antitumor efficacy in vivo. Mechanistically, scRNA-seq demonstrated that cGAS EVs mediated significant remodeling of intratumoral microenvironment, revealing a pivotal role of infiltrating neutrophils in the antitumor immune milieu. Collectively, IDEA, as a universal and facile strategy, can be applied to expand and advance the development of protein-based therapeutics.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":"724-743"},"PeriodicalIF":13.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140190063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Protein & CellPub Date : 2024-10-01DOI: 10.1093/procel/pwae010
Dandan Feng, Jie Gao, Ruiqiong Liu, Wei Liu, Tianyang Gao, Yunkai Yang, Die Zhang, Tianshu Yang, Xin Yin, Hefen Yu, Wei Huang, Yan Wang
{"title":"CARM1 drives triple-negative breast cancer progression by coordinating with HIF1A.","authors":"Dandan Feng, Jie Gao, Ruiqiong Liu, Wei Liu, Tianyang Gao, Yunkai Yang, Die Zhang, Tianshu Yang, Xin Yin, Hefen Yu, Wei Huang, Yan Wang","doi":"10.1093/procel/pwae010","DOIUrl":"10.1093/procel/pwae010","url":null,"abstract":"<p><p>Coactivator-associated arginine methyltransferase 1 (CARM1) promotes the development and metastasis of estrogen receptor alpha (ERα)-positive breast cancer. The function of CARM1 in triple-negative breast cancer (TNBC) is still unclear and requires further exploration. Here, we report that CARM1 promotes proliferation, epithelial-mesenchymal transition, and stemness in TNBC. CARM1 is upregulated in multiple cancers and its expression correlates with breast cancer progression. Genome-wide analysis of CARM1 showed that CARM1 is recruited by hypoxia-inducible factor-1 subunit alpha (HIF1A) and occupy the promoters of CDK4, Cyclin D1, β-Catenin, HIF1A, MALAT1, and SIX1 critically involved in cell cycle, HIF-1 signaling pathway, Wnt signaling pathway, VEGF signaling pathway, thereby modulating the proliferation and invasion of TNBC cells. We demonstrated that CARM1 is physically associated with and directly interacts with HIF1A. Moreover, we found that ellagic acid, an inhibitor of CARM1, can suppress the proliferation and invasion of TNBC by directly inhibiting CDK4 expression. Our research has determined the molecular basis of CARM1 carcinogenesis in TNBC and its effective natural inhibitor, which may provide new ideas and drugs for cancer therapy.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":"744-765"},"PeriodicalIF":13.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140111272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"NudCL2 is required for cytokinesis by stabilizing RCC2 with Hsp90 at the midbody.","authors":"Xiaoyang Xu, Yuliang Huang, Feng Yang, Xiaoxia Sun, Rijin Lin, Jiaxing Feng, Mingyang Yang, Jiaqi Shao, Xiaoqi Liu, Tianhua Zhou, Shanshan Xie, Yuehong Yang","doi":"10.1093/procel/pwae025","DOIUrl":"10.1093/procel/pwae025","url":null,"abstract":"<p><p>Cytokinesis is required for faithful division of cytoplasmic components and duplicated nuclei into two daughter cells. Midbody, a protein-dense organelle that forms at the intercellular bridge, is indispensable for successful cytokinesis. However, the regulatory mechanism of cytokinesis at the midbody still remains elusive. Here, we unveil a critical role for NudC-like protein 2 (NudCL2), a co-chaperone of heat shock protein 90 (Hsp90), in cytokinesis regulation by stabilizing regulator of chromosome condensation 2 (RCC2) at the midbody in mammalian cells. NudCL2 localizes at the midbody, and its downregulation results in cytokinesis failure, multinucleation, and midbody disorganization. Using iTRAQ-based quantitative proteomic analysis, we find that RCC2 levels are decreased in NudCL2 knockout (KO) cells. Moreover, Hsp90 forms a complex with NudCL2 to stabilize RCC2, which is essential for cytokinesis. RCC2 depletion mirrors phenotypes observed in NudCL2-downregulated cells. Importantly, ectopic expression of RCC2 rescues the cytokinesis defects induced by NudCL2 deletion, but not vice versa. Together, our data reveal the significance of the NudCL2/Hsp90/RCC2 pathway in cytokinesis at the midbody.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":"766-782"},"PeriodicalIF":13.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141154676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Protein & CellPub Date : 2024-09-27DOI: 10.1093/procel/pwae053
Xiufang Xiong,Yongchao Zhao,Yi Sun
{"title":"SMURF1: A promising target for colon cancer therapy.","authors":"Xiufang Xiong,Yongchao Zhao,Yi Sun","doi":"10.1093/procel/pwae053","DOIUrl":"https://doi.org/10.1093/procel/pwae053","url":null,"abstract":"","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":"36 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329093","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":"PDHX acetylation facilitates tumor progression by disrupting PDC assembly and activating lactylation mediated gene expression.","authors":"Zetan Jiang, Nanchi Xiong, Ronghui Yan, Shi-Ting Li, Haiying Liu, Qiankun Mao, Yuchen Sun, Shengqi Shen, Ling Ye, Ping Gao, Pinggen Zhang, Weidong Jia, Huafeng Zhang","doi":"10.1093/procel/pwae052","DOIUrl":"https://doi.org/10.1093/procel/pwae052","url":null,"abstract":"<p><p>Deactivation of the mitochondrial pyruvate dehydrogenase complex (PDC) is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis. Studies examining PDC activity regulation have mainly focused on the phosphorylation of pyruvate dehydrogenase (PDH, E1), leaving other post-translational modifications (PTMs) largely unexplored. Here, we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X (PDHX) commonly occurs in hepatocellular carcinoma (HCC), disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression. PDHX, an E3-binding protein (E3BP) in the PDC, is acetylated by the p300 at Lys 488, impeding the interaction between PDHX and dihydrolipoyl transacetylase (DLAT, E2), thereby disrupting PDC assembly to inhibit its activation. PDC disruption results in the conversion of most glucose to lactate, contributing to the aerobic glycolysis and H3K56 lactylation-mediated gene expression, facilitating tumor progression. These findings highlight a previously unrecognized role of PDHX acetylation in regulating PDC assembly and activity, linking PDHX Lys 488 acetylation and histone lactylation during HCC progression and providing a potential biomarker and therapeutic target for further development.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142293998","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":"ER membrane remodeling by targeting RTN4 induces pyroptosis to facilitate antitumor immune.","authors":"Mei-Mei Zhao,Ting-Ting Ren,Jing-Kang Wang,Lu Yao,Ting-Ting Liu,Ji-Chao Zhang,Yang Liu,Lan Yuan,Dan Liu,Jiu-Hui Xu,Peng-Fei Tu,Xiao-Dong Tang,Ke-Wu Zeng","doi":"10.1093/procel/pwae049","DOIUrl":"https://doi.org/10.1093/procel/pwae049","url":null,"abstract":"Pyroptosis is an identified programmed cell death that has been highly linked to endoplasmic reticulum (ER) dynamics. However, the crucial proteins for modulating dynamic ER membrane curvature change that trigger pyroptosis are currently not well understood. In this study, a biotin-labeled chemical probe of potent pyroptosis inducer α-mangostin (α-MG) was synthesized. Through protein microarray analysis, reticulon-4 (RTN4/Nogo), a crucial regulator of ER membrane curvature, was identified as a target of α-MG. We observed that chemically induced proteasome degradation of RTN4 by α-MG through recruiting E3 ligase UBR5 significantly enhances the pyroptosis phenotype in cancer cells. Interestingly, the downregulation of RTN4 expression significantly facilitated a dynamic remodeling of ER membrane curvature through a transition from tubules to sheets, consequently leading to rapid fusion of the ER with the cell plasma membrane. In particular, the ER-to-plasma membrane fusion process is supported by the observed translocation of several crucial ER markers to the \"bubble\" structures of pyroptotic cells. Furthermore, α-MG-induced RTN4 knockdown leads to PKM2-dependent conventional caspase-3/GSDME cleavages for pyroptosis progression. In vivo, we observed that chemical or genetic RTN4 knockdown significantly inhibited cancer cells growth, which further exhibited an antitumor immune response with anti-PD-1. In translational research, RTN4 high expression was closely correlated with the tumor metastasis and death of patients. Taken together, RTN4 plays a fundamental role in inducing pyroptosis through the modulation of ER membrane curvature remodeling, thus representing a prospective druggable target for anticancer immunotherapy.","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":"48 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142165961","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}
Protein & CellPub Date : 2024-09-03DOI: 10.1093/procel/pwae048
Heng Zhang, Zhiwei Zheng, Xiaoying Chen, Lizhen Xu, Chen Guo, Jiawei Wang, Yihui Cui, Fan Yang
{"title":"RADICAL: a rationally designed ion channel activated by ligand for chemogenetics.","authors":"Heng Zhang, Zhiwei Zheng, Xiaoying Chen, Lizhen Xu, Chen Guo, Jiawei Wang, Yihui Cui, Fan Yang","doi":"10.1093/procel/pwae048","DOIUrl":"https://doi.org/10.1093/procel/pwae048","url":null,"abstract":"","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120399","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}
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