ECSIT Is a Critical Factor for Controlling Intestinal Homeostasis and Tumorigenesis through Regulating the Translation of YAP Protein
Abstract The intestinal epithelium is the fastest renewing tissue in mammals and its regenerative process must be tightly controlled to minimize the risk of dysfunction and tumorigenesis. The orderly expression and activation of Yes‐associated protein (YAP) are the key steps in driving intestinal re...
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-09-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202205180 |
| _version_ | 1827824712233779200 |
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| author | Yuying Jiang Chunmei Ma Yingchao Hu Yongbing Yang Chanyuan Ma Chunyan Wu Lu Liu Shuang Wen Paul N. Moynagh Bingwei Wang Shuo Yang |
| author_facet | Yuying Jiang Chunmei Ma Yingchao Hu Yongbing Yang Chanyuan Ma Chunyan Wu Lu Liu Shuang Wen Paul N. Moynagh Bingwei Wang Shuo Yang |
| author_sort | Yuying Jiang |
| collection | DOAJ |
| description | Abstract The intestinal epithelium is the fastest renewing tissue in mammals and its regenerative process must be tightly controlled to minimize the risk of dysfunction and tumorigenesis. The orderly expression and activation of Yes‐associated protein (YAP) are the key steps in driving intestinal regeneration and crucial for intestinal homeostasis. However, the regulatory mechanisms controlling this process remain largely unknown. Here, it is discovered that evolutionarily conserved signaling intermediate in Toll pathways (ECSIT), a multi‐functional protein, is enriched along the crypt–villus axis. Intestinal cell‐specific ablation of ECSIT results in the dysregulation of intestinal differentiation unexpectedly accompanied with enhanced YAP protein dependent on translation, thus transforming intestinal cells to early proliferative stem “‐like” cells and augmenting intestinal tumorigenesis. Loss of ECSIT leads to metabolic reprogramming in favor of amino acid–based metabolism, which results in demethylation of genes encoding the eukaryotic initiation factor 4F pathway and their increased expression that further promotes YAP translation initiation culminating in intestinal homeostasis imbalance and tumorigenesis. It is also shown that the expression of ECSIT is positively correlated with the survival of patients with colorectal cancer. Together, these results demonstrate the important role of ECSIT in regulating YAP protein translation to control intestinal homeostasis and tumorigenesis. |
| first_indexed | 2024-03-12T02:31:40Z |
| format | Article |
| id | doaj.art-2b2c4b0ccb1c48348c5a12a4a33bec85 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-12T02:31:40Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-2b2c4b0ccb1c48348c5a12a4a33bec852023-09-05T07:49:09ZengWileyAdvanced Science2198-38442023-09-011025n/an/a10.1002/advs.202205180ECSIT Is a Critical Factor for Controlling Intestinal Homeostasis and Tumorigenesis through Regulating the Translation of YAP ProteinYuying Jiang0Chunmei Ma1Yingchao Hu2Yongbing Yang3Chanyuan Ma4Chunyan Wu5Lu Liu6Shuang Wen7Paul N. Moynagh8Bingwei Wang9Shuo Yang10Department of Immunology State Key Laboratory of Reproductive Medicine and Offspring Health Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Collaborative Innovation Center for Personalized Cancer Medicine Gusu School The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Nanjing Medical University Nanjing 211166 ChinaDepartment of Immunology State Key Laboratory of Reproductive Medicine and Offspring Health Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Collaborative Innovation Center for Personalized Cancer Medicine Gusu School The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Nanjing Medical University Nanjing 211166 ChinaDepartment of Immunology State Key Laboratory of Reproductive Medicine and Offspring Health Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Collaborative Innovation Center for Personalized Cancer Medicine Gusu School The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Nanjing Medical University Nanjing 211166 ChinaDepartment of Immunology State Key Laboratory of Reproductive Medicine and Offspring Health Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Collaborative Innovation Center for Personalized Cancer Medicine Gusu School The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Nanjing Medical University Nanjing 211166 ChinaDepartment of Immunology State Key Laboratory of Reproductive Medicine and Offspring Health Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Collaborative Innovation Center for Personalized Cancer Medicine Gusu School The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Nanjing Medical University Nanjing 211166 ChinaDepartment of Immunology State Key Laboratory of Reproductive Medicine and Offspring Health Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Collaborative Innovation Center for Personalized Cancer Medicine Gusu School The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Nanjing Medical University Nanjing 211166 ChinaDepartment of Immunology State Key Laboratory of Reproductive Medicine and Offspring Health Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Collaborative Innovation Center for Personalized Cancer Medicine Gusu School The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Nanjing Medical University Nanjing 211166 ChinaDepartment of Immunology State Key Laboratory of Reproductive Medicine and Offspring Health Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Collaborative Innovation Center for Personalized Cancer Medicine Gusu School The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Nanjing Medical University Nanjing 211166 ChinaKathleen Lonsdale Institute for Human Health Research Department of Biology National University of Ireland Maynooth Maynooth W23 F2H6 IrelandDepartment of Pharmacology Nanjing University of Chinese Medicine 138 Xianlin Avenue Nanjing 210023 ChinaDepartment of Immunology State Key Laboratory of Reproductive Medicine and Offspring Health Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Collaborative Innovation Center for Personalized Cancer Medicine Gusu School The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Nanjing Medical University Nanjing 211166 ChinaAbstract The intestinal epithelium is the fastest renewing tissue in mammals and its regenerative process must be tightly controlled to minimize the risk of dysfunction and tumorigenesis. The orderly expression and activation of Yes‐associated protein (YAP) are the key steps in driving intestinal regeneration and crucial for intestinal homeostasis. However, the regulatory mechanisms controlling this process remain largely unknown. Here, it is discovered that evolutionarily conserved signaling intermediate in Toll pathways (ECSIT), a multi‐functional protein, is enriched along the crypt–villus axis. Intestinal cell‐specific ablation of ECSIT results in the dysregulation of intestinal differentiation unexpectedly accompanied with enhanced YAP protein dependent on translation, thus transforming intestinal cells to early proliferative stem “‐like” cells and augmenting intestinal tumorigenesis. Loss of ECSIT leads to metabolic reprogramming in favor of amino acid–based metabolism, which results in demethylation of genes encoding the eukaryotic initiation factor 4F pathway and their increased expression that further promotes YAP translation initiation culminating in intestinal homeostasis imbalance and tumorigenesis. It is also shown that the expression of ECSIT is positively correlated with the survival of patients with colorectal cancer. Together, these results demonstrate the important role of ECSIT in regulating YAP protein translation to control intestinal homeostasis and tumorigenesis.https://doi.org/10.1002/advs.202205180evolutionarily conserved signaling intermediate in Toll pathwaysintestinal differentiation and tumorigenesisYAP |
| spellingShingle | Yuying Jiang Chunmei Ma Yingchao Hu Yongbing Yang Chanyuan Ma Chunyan Wu Lu Liu Shuang Wen Paul N. Moynagh Bingwei Wang Shuo Yang ECSIT Is a Critical Factor for Controlling Intestinal Homeostasis and Tumorigenesis through Regulating the Translation of YAP Protein Advanced Science evolutionarily conserved signaling intermediate in Toll pathways intestinal differentiation and tumorigenesis YAP |
| title | ECSIT Is a Critical Factor for Controlling Intestinal Homeostasis and Tumorigenesis through Regulating the Translation of YAP Protein |
| title_full | ECSIT Is a Critical Factor for Controlling Intestinal Homeostasis and Tumorigenesis through Regulating the Translation of YAP Protein |
| title_fullStr | ECSIT Is a Critical Factor for Controlling Intestinal Homeostasis and Tumorigenesis through Regulating the Translation of YAP Protein |
| title_full_unstemmed | ECSIT Is a Critical Factor for Controlling Intestinal Homeostasis and Tumorigenesis through Regulating the Translation of YAP Protein |
| title_short | ECSIT Is a Critical Factor for Controlling Intestinal Homeostasis and Tumorigenesis through Regulating the Translation of YAP Protein |
| title_sort | ecsit is a critical factor for controlling intestinal homeostasis and tumorigenesis through regulating the translation of yap protein |
| topic | evolutionarily conserved signaling intermediate in Toll pathways intestinal differentiation and tumorigenesis YAP |
| url | https://doi.org/10.1002/advs.202205180 |
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