Pub Date : 2025-11-21DOI: 10.1038/s41418-025-01613-5
Sabrina Zema, Francesca Di Fazio, Maria Pelullo, Sara Di Savino, Bruna Cerbelli, Martina Leopizzi, Laura Di Magno, Carmine Nicoletti, Giovanna Peruzzi, Daniel D’Andrea, Maria V. Giuli, Samantha Cialfi, Biagio Palmisano, Alice Turdo, Rocco Palermo, Giulia d’Amati, Gianluca Canettieri, Antongiulio Faggiano, Lucia Di Marcotullio, Matilde Todaro, Isabella Screpanti, Claudio Talora, Saula Checquolo, Diana Bellavia
Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous breast cancer subtype with poor patient outcomes. TNBC heterogeneity arises from multiple dysregulated pathways, including Notch and Hedgehog, which contribute to tumor initiation, progression, and drug resistance. Identifying common molecular regulators of TNBC aggressiveness is crucial for developing effective therapeutic strategies. Here, we demonstrate that the transcriptional coactivator MAML1 drives TNBC aggressiveness by regulating Notch1 and Gli1 stability through the E3 ubiquitin ligase Itch, functioning as an Itch-negative regulator. Mechanistically, MAML1 interacts with Itch via its PPQY motif and promotes K63-linked self-ubiquitylation of Itch, deregulating its expression/activity. Using a Maml1-deficient mouse model, we reveal an inverse correlation between MAML1 and Itch levels, where the loss of MAML1 stabilizes Itch and suppresses Notch1 and Gli1 activity. Conversely, MAML1 upregulation enhances Notch1 and Gli1 expression, driving accelerated TNBC tumor growth and faster multiorgan metastasis in vivo. Accordingly, we show that MAML1 is overexpressed in a cohort of TNBC patients, and the combined overexpression of MAML1/Notch1 and MAML1/Gli1 correlates with poor clinical outcomes by in silico analysis. Our findings establish a dual role for MAML1 as a transcriptional coactivator and a post-translational regulator of Itch, thereby amplifying Notch and Hedgehog oncogenic signaling. This study uncovers MAML1 as a key driver of TNBC progression and a potential therapeutic target for fighting TNBC aggressiveness and heterogeneity.
{"title":"MAML1 drives Notch and Hedgehog oncogenic pathways by inhibiting Itch activity in triple-negative breast cancer","authors":"Sabrina Zema, Francesca Di Fazio, Maria Pelullo, Sara Di Savino, Bruna Cerbelli, Martina Leopizzi, Laura Di Magno, Carmine Nicoletti, Giovanna Peruzzi, Daniel D’Andrea, Maria V. Giuli, Samantha Cialfi, Biagio Palmisano, Alice Turdo, Rocco Palermo, Giulia d’Amati, Gianluca Canettieri, Antongiulio Faggiano, Lucia Di Marcotullio, Matilde Todaro, Isabella Screpanti, Claudio Talora, Saula Checquolo, Diana Bellavia","doi":"10.1038/s41418-025-01613-5","DOIUrl":"https://doi.org/10.1038/s41418-025-01613-5","url":null,"abstract":"Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous breast cancer subtype with poor patient outcomes. TNBC heterogeneity arises from multiple dysregulated pathways, including Notch and Hedgehog, which contribute to tumor initiation, progression, and drug resistance. Identifying common molecular regulators of TNBC aggressiveness is crucial for developing effective therapeutic strategies. Here, we demonstrate that the transcriptional coactivator MAML1 drives TNBC aggressiveness by regulating Notch1 and Gli1 stability through the E3 ubiquitin ligase Itch, functioning as an Itch-negative regulator. Mechanistically, MAML1 interacts with Itch <jats:italic>via</jats:italic> its PPQY motif and promotes K63-linked self-ubiquitylation of Itch, deregulating its expression/activity. Using a Maml1-deficient mouse model, we reveal an inverse correlation between MAML1 and Itch levels, where the loss of MAML1 stabilizes Itch and suppresses Notch1 and Gli1 activity. Conversely, MAML1 upregulation enhances Notch1 and Gli1 expression, driving accelerated TNBC tumor growth and faster multiorgan metastasis in vivo. Accordingly, we show that MAML1 is overexpressed in a cohort of TNBC patients, and the combined overexpression of MAML1/Notch1 and MAML1/Gli1 correlates with poor clinical outcomes by in silico analysis. Our findings establish a dual role for MAML1 as a transcriptional coactivator and a post-translational regulator of Itch, thereby amplifying Notch and Hedgehog oncogenic signaling. This study uncovers MAML1 as a key driver of TNBC progression and a potential therapeutic target for fighting TNBC aggressiveness and heterogeneity.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"188 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567395","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}
Pub Date : 2025-11-19DOI: 10.1038/s41418-025-01598-1
Sonia S. Shah, Jantina A. Manning, Yoon Lim, Diva Sinha, Ambika Mosale Venkatesh Murthy, Raja Ganesan, Nirmal Robinson, Emad S. Alnemri, Seth L. Masters, James E. Vince, Sharad Kumar
The membrane pore-forming gasdermin (GSDM) proteins are essential executors of pyroptosis. The GSDM family members GSDMD and GSDME can also target mitochondrial membranes, driving apoptosis. Here, we identify the ubiquitin ligase NEDD4L as a key regulator of GSDMD and GSDME, two GSDMs involved in cell death. NEDD4L ubiquitinates both these proteins to control their stability and intracellular expression levels. Knockout of mouse Nedd4l (also called Nedd4-2 ) results in lung and kidney damage with perinatal lethality within three weeks of birth. These mice demonstrated elevated GSDMD in alveolar epithelia and increased GSDME in kidney tubular epithelia, suggesting tissue-specific regulation by NEDD4L. Renal tubule-specific Nedd4l knockout mice showed GSDM activation, tubular cell death and reduced kidney function after high sodium diet. NEDD4L-deficient cells showed increased GSDM activation, IL-1β release and were significantly more susceptible to cell death induced by NLRP3 agonists, cytotoxic agents, and bacterial infection. These results demonstrate that NEDD4L regulates GSDMD and GSDME functions by preventing their accumulation and reveals an unexplored link between GSDM stability and cell death.
{"title":"NEDD4L-mediated Gasdermin D and E ubiquitination regulates cell death and tissue injury","authors":"Sonia S. Shah, Jantina A. Manning, Yoon Lim, Diva Sinha, Ambika Mosale Venkatesh Murthy, Raja Ganesan, Nirmal Robinson, Emad S. Alnemri, Seth L. Masters, James E. Vince, Sharad Kumar","doi":"10.1038/s41418-025-01598-1","DOIUrl":"https://doi.org/10.1038/s41418-025-01598-1","url":null,"abstract":"The membrane pore-forming gasdermin (GSDM) proteins are essential executors of pyroptosis. The GSDM family members GSDMD and GSDME can also target mitochondrial membranes, driving apoptosis. Here, we identify the ubiquitin ligase NEDD4L as a key regulator of GSDMD and GSDME, two GSDMs involved in cell death. NEDD4L ubiquitinates both these proteins to control their stability and intracellular expression levels. Knockout of mouse <jats:italic>Nedd4l</jats:italic> (also called <jats:italic>Nedd4-2</jats:italic> ) results in lung and kidney damage with perinatal lethality within three weeks of birth. These mice demonstrated elevated GSDMD in alveolar epithelia and increased GSDME in kidney tubular epithelia, suggesting tissue-specific regulation by NEDD4L. Renal tubule-specific <jats:italic>Nedd4l</jats:italic> knockout mice showed GSDM activation, tubular cell death and reduced kidney function after high sodium diet. NEDD4L-deficient cells showed increased GSDM activation, IL-1β release and were significantly more susceptible to cell death induced by NLRP3 agonists, cytotoxic agents, and bacterial infection. These results demonstrate that NEDD4L regulates GSDMD and GSDME functions by preventing their accumulation and reveals an unexplored link between GSDM stability and cell death.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"158 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554414","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":"HERP constrains white adipose expansion and inflammation by STEAP4 stabilization","authors":"Yingchun Chen, Yanyan Wu, Haorui Qin, Zhiqiang Han, Yao Tang, Qiuyan Wang, Fei Xiao","doi":"10.1038/s41418-025-01608-2","DOIUrl":"https://doi.org/10.1038/s41418-025-01608-2","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"11 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536151","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}
Pub Date : 2025-11-11DOI: 10.1038/s41418-025-01616-2
Francesco Napoletano, Rebecca Bertolio, Giannino Del Sal
{"title":"Ubiquitin choreography in nasopharyngeal carcinoma: USP18 scaffolds radioresistance","authors":"Francesco Napoletano, Rebecca Bertolio, Giannino Del Sal","doi":"10.1038/s41418-025-01616-2","DOIUrl":"https://doi.org/10.1038/s41418-025-01616-2","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"22 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492632","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}
Radiotherapy, which induces DNA damage to control the progression of local tumors, is the mainstay therapy for nasopharyngeal carcinoma (NPC). However, almost a fifth of patients undergo recurrence. Evidence suggests that ubiquitination is crucial in DNA damage repair (DDR) signaling. In this study, we reveal that the ubiquitin specific peptidase 18 (USP18) is significantly overexpressed in resistant NPC tissues and correlates inversely with NPC cell radiosensitivity. Our findings indicate that USP18 interacts with tripartite motif containing 29 (TRIM29), facilitating its K27-linked ubiquitination independent of USP18’s catalytic activity. USP18 functions as a scaffold, recruiting the E3 ubiquitin ligase tripartite motif containing 21 (TRIM21), which directly ubiquitinates TRIM29 at Lys561. This process promotes TRIM29 oligomerization and nuclear translocation, which enhances DDR in NPC cells after radiotherapy. Clinically, high USP18 levels are associated with worse patient prognosis. Our findings underscore the critical role of USP18 in modulating DDR signaling and radiosensitivity in NPC, suggesting that targeting the USP18-TRIM21-TRIM29 axis may represent a novel strategy to enhance the efficacy of radiotherapy for patients with NPC.
{"title":"USP18 promotes nasopharyngeal carcinoma radioresistance via TRIM29 oligomerization and ubiquitination","authors":"Jia-Yi Lin, Jun-Xiang Chen, Zi-Chen Qiu, Wei-Wei Zhang, Qing-Jie Li, Jun-Yan Li, Xu Jiang, Yu-Han Hu, Shi-Wei He, Shan Zhang, Ying-Qin Li, Na Liu, Jun Ma, Yin Zhao, Rui Guo","doi":"10.1038/s41418-025-01615-3","DOIUrl":"https://doi.org/10.1038/s41418-025-01615-3","url":null,"abstract":"Radiotherapy, which induces DNA damage to control the progression of local tumors, is the mainstay therapy for nasopharyngeal carcinoma (NPC). However, almost a fifth of patients undergo recurrence. Evidence suggests that ubiquitination is crucial in DNA damage repair (DDR) signaling. In this study, we reveal that the ubiquitin specific peptidase 18 (USP18) is significantly overexpressed in resistant NPC tissues and correlates inversely with NPC cell radiosensitivity. Our findings indicate that USP18 interacts with tripartite motif containing 29 (TRIM29), facilitating its K27-linked ubiquitination independent of USP18’s catalytic activity. USP18 functions as a scaffold, recruiting the E3 ubiquitin ligase tripartite motif containing 21 (TRIM21), which directly ubiquitinates TRIM29 at Lys561. This process promotes TRIM29 oligomerization and nuclear translocation, which enhances DDR in NPC cells after radiotherapy. Clinically, high USP18 levels are associated with worse patient prognosis. Our findings underscore the critical role of USP18 in modulating DDR signaling and radiosensitivity in NPC, suggesting that targeting the USP18-TRIM21-TRIM29 axis may represent a novel strategy to enhance the efficacy of radiotherapy for patients with NPC.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"163 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492633","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}
Pub Date : 2025-11-11DOI: 10.1038/s41418-025-01614-4
Yan Gao, Zhuo Zhao, Xuepin Chen, Nuo Li, Ying Li, Jun Guan, Hongyan Dai
{"title":"RNF220 mediates K63-linked polyubiquitination of STAT3 and aggravates pathological cardiac hypertrophy","authors":"Yan Gao, Zhuo Zhao, Xuepin Chen, Nuo Li, Ying Li, Jun Guan, Hongyan Dai","doi":"10.1038/s41418-025-01614-4","DOIUrl":"https://doi.org/10.1038/s41418-025-01614-4","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"29 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145484714","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}
Pub Date : 2025-11-08DOI: 10.1038/s41418-025-01612-6
Diyun Xu, Jibo Han, Bozhi Ye, Liming Lin, Jiaji Chen, Yanhong Jin, Ying Zhao, Yi Wang, Peiren Shan, Guang Liang
{"title":"USP13 ameliorates diabetic cardiomyopathy via deubiquitinating NLRP3 and inhibiting pyroptosis in cardiomyocytes","authors":"Diyun Xu, Jibo Han, Bozhi Ye, Liming Lin, Jiaji Chen, Yanhong Jin, Ying Zhao, Yi Wang, Peiren Shan, Guang Liang","doi":"10.1038/s41418-025-01612-6","DOIUrl":"https://doi.org/10.1038/s41418-025-01612-6","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"82 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462326","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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