The growth of Caenorhabditis elegans involves multiple molting processes,during which old cuticles are shed and new cuticles are rapidly formed.This process requires the regulated bulk secretion of cuticle components....The growth of Caenorhabditis elegans involves multiple molting processes,during which old cuticles are shed and new cuticles are rapidly formed.This process requires the regulated bulk secretion of cuticle components.The transmembrane protein-39(TMEM-39)mutant exhibits distinct dumpy and ruptured phenotypes characterized by notably thin cuticles.TMEM-39 primarily co-localizes with the coat protein II complex(COPII)in large vesicles rather than small COPII vesicles.These TMEM-39-associated large vesicles(TMEM-39-LVs)form robustly during the molting period and co-localize with various extracellular matrix components,including BLI-1 collagen,BLI-3 dual oxidase,and carboxypeptidases.Through immunoprecipitation using TMEM39A-FLAG and proteomics analysis in human sarcoma cells,we identify TMEM39A-associated proteins,including TMEM131.Knockdown of TMEM131 results in reduced TMEM39A-LV formation and collagen secretion in both C.elegans and human sarcoma cells,indicating a cooperative role between TMEM39A and TMEM131 in the secretion of extracellular components through the formation of large COPII vesicles.Given the conservation of TMEM39A and its associated proteins between C.elegans and humans,TMEM39A-LVs may represent a fundamental machinery for rapid and extensive secretion across metazoans.展开更多
Colorectal tumorigenesis generally progresses from adenoma to adenocarcinoma,accompanied by dynamic changes in the tumor microenvironment(TME).A randomized controlled trial has confirmed the efficacy and safety of She...Colorectal tumorigenesis generally progresses from adenoma to adenocarcinoma,accompanied by dynamic changes in the tumor microenvironment(TME).A randomized controlled trial has confirmed the efficacy and safety of Shen-Bai-Jie-Du decoction(SBJDD)in preventing colorectal tumorigenesis.However,the mechanism remains unclear.In this study,we employed single-cell RNA sequencing(scRNA-seq)to investigate the dynamic evolution of the TME and validated cell infiltration with multiplex immunohistochemistry and flow cytometry.Bulk RNA sequencing was utilized to assess the underlying mechanisms.Our results constructed the mutually verifiable single-cell transcriptomic atlases in Apc^(Min/+)mice and clinical patients.There was a marked accumulation of CCL22^(+)dendritic cells(DCs)and an enhanced immunosuppressive action,which SBJDD and berberine reversed.Combined treatment with cholesterol and lipopolysaccharide induced characteristic gene expression of CCL22^(+)DCs,which may represent“exhausted DCs”.Intraperitoneal injection of these DCs after SBJDD treatment eliminated its therapeutic effects.TMEM131 derived CCL22+DCs generation by TNF signaling pathway and may be a potential target of berberine in retarding colorectal tumorigenesis.These findings emphasize the role of exhausted DCs and the regulatory mechanisms of SBJDD and berberine in colorectal cancer(CRC),suggesting that the multi-component properties of SBJDD may help restore TME homeostasis and offer novel cancer therapy.展开更多
基金supported by the National Institutes of Health-Office of Research Infrastructure Programs(P40 OD010440)supported in part by grants from the National Cancer Center of Korea(NCC-2110160,NCC-2110263,and NCC-2310750)supported by the Basic Science Research Program of the National Research Foundation of Korea,funded by the Ministry of Science,ICT,and Future Planning(NRF-2015R1C1A1A01053611).
文摘The growth of Caenorhabditis elegans involves multiple molting processes,during which old cuticles are shed and new cuticles are rapidly formed.This process requires the regulated bulk secretion of cuticle components.The transmembrane protein-39(TMEM-39)mutant exhibits distinct dumpy and ruptured phenotypes characterized by notably thin cuticles.TMEM-39 primarily co-localizes with the coat protein II complex(COPII)in large vesicles rather than small COPII vesicles.These TMEM-39-associated large vesicles(TMEM-39-LVs)form robustly during the molting period and co-localize with various extracellular matrix components,including BLI-1 collagen,BLI-3 dual oxidase,and carboxypeptidases.Through immunoprecipitation using TMEM39A-FLAG and proteomics analysis in human sarcoma cells,we identify TMEM39A-associated proteins,including TMEM131.Knockdown of TMEM131 results in reduced TMEM39A-LV formation and collagen secretion in both C.elegans and human sarcoma cells,indicating a cooperative role between TMEM39A and TMEM131 in the secretion of extracellular components through the formation of large COPII vesicles.Given the conservation of TMEM39A and its associated proteins between C.elegans and humans,TMEM39A-LVs may represent a fundamental machinery for rapid and extensive secretion across metazoans.
基金supported by the National Key R&D Program of China(2022YFC3500200,2022YFC3500202)National Natural Science Foundation of China(U24A20794,82103197)+4 种基金Jiangsu Province Postgraduate Training Innovation Project Grant(KYCX23_2132,China)the Integrated Traditional Chinese and Western Medicine Clinical Medicine Innovation Center Fund for Colorectal Polyps from Jiangsu Province Hospital of Chinese Medicine(No.Y2023zx10)the project funding from Jiangsu Province Hospital of Chinese Medicine(No.kgr0253,China)Natural Science Foundation of Jiangsu Province(BK20210686,China)Nanjing University of Chinese Medicine’s Key Project:“Leading the Charge with Open Competition”(AD202405,China).
文摘Colorectal tumorigenesis generally progresses from adenoma to adenocarcinoma,accompanied by dynamic changes in the tumor microenvironment(TME).A randomized controlled trial has confirmed the efficacy and safety of Shen-Bai-Jie-Du decoction(SBJDD)in preventing colorectal tumorigenesis.However,the mechanism remains unclear.In this study,we employed single-cell RNA sequencing(scRNA-seq)to investigate the dynamic evolution of the TME and validated cell infiltration with multiplex immunohistochemistry and flow cytometry.Bulk RNA sequencing was utilized to assess the underlying mechanisms.Our results constructed the mutually verifiable single-cell transcriptomic atlases in Apc^(Min/+)mice and clinical patients.There was a marked accumulation of CCL22^(+)dendritic cells(DCs)and an enhanced immunosuppressive action,which SBJDD and berberine reversed.Combined treatment with cholesterol and lipopolysaccharide induced characteristic gene expression of CCL22^(+)DCs,which may represent“exhausted DCs”.Intraperitoneal injection of these DCs after SBJDD treatment eliminated its therapeutic effects.TMEM131 derived CCL22+DCs generation by TNF signaling pathway and may be a potential target of berberine in retarding colorectal tumorigenesis.These findings emphasize the role of exhausted DCs and the regulatory mechanisms of SBJDD and berberine in colorectal cancer(CRC),suggesting that the multi-component properties of SBJDD may help restore TME homeostasis and offer novel cancer therapy.
