Activation of APOBEC3 cytidine deaminases and endogenous retroviruses is integrated by MUC1-C in NSCLC cells
Abstract The APOBEC3 (A3) genes encoding cytidine deaminases evolved in mammals to restrict retroviral replication. The MUC1 gene appeared in mammals to protect barrier tissues from viral infections. There is no known involvement of the MUC1 encoded MUC1-C/M1C protein in the regulation of A3s. We fo...
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| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-08-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02673-9 |
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| author | Naoki Haratake Shinkichi Takamori Hideko Isozaki Keisuke Shigeta Chie Kikutake Hiroki Ozawa Atrayee Bhattacharya Ayako Nakashoji Mikita Suyama Tomoyoshi Takenaka Tomoharu Yoshizumi Atsushi Osoegawa Aaron N. Hata Donald Kufe |
| author_facet | Naoki Haratake Shinkichi Takamori Hideko Isozaki Keisuke Shigeta Chie Kikutake Hiroki Ozawa Atrayee Bhattacharya Ayako Nakashoji Mikita Suyama Tomoyoshi Takenaka Tomoharu Yoshizumi Atsushi Osoegawa Aaron N. Hata Donald Kufe |
| author_sort | Naoki Haratake |
| collection | DOAJ |
| description | Abstract The APOBEC3 (A3) genes encoding cytidine deaminases evolved in mammals to restrict retroviral replication. The MUC1 gene appeared in mammals to protect barrier tissues from viral infections. There is no known involvement of the MUC1 encoded MUC1-C/M1C protein in the regulation of A3s. We found that induction of MUC1-C in NSCLC cells treated with EGFR inhibitors integrates activation of an inflammatory memory response with the type I interferon (IFN) STAT1/STAT2/IRF9 (U-ISGF3) pathway. In turn, MUC1-C drives expression of A3 genes by activating their U-ISGF3-stimulated response elements (ISREs). We also report that MUC1-C-mediated induction of type II IFN STAT1 homodimer (U-GAF) complexes and the gamma-associated signaling (GAS) pathway drives human endogenous retrovirus HERV-K102/K108 expression. Our results in NSCLC cell line and patient-derived models further demonstrate that MUC1-C activates A3 and HERV-K expression by a common MUC1-C→STAT1 auto-inductive pathway. These previously unrecognized findings demonstrate that a MUC1-C-driven inflammatory pathway coordinates activation of APOBEC3 and HERV-K expression. |
| format | Article |
| id | doaj-art-e62311c0e7ae4926bc07209f285c4914 |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-e62311c0e7ae4926bc07209f285c49142025-08-20T04:01:46ZengNature Publishing GroupCell Death Discovery2058-77162025-08-0111111410.1038/s41420-025-02673-9Activation of APOBEC3 cytidine deaminases and endogenous retroviruses is integrated by MUC1-C in NSCLC cellsNaoki Haratake0Shinkichi Takamori1Hideko Isozaki2Keisuke Shigeta3Chie Kikutake4Hiroki Ozawa5Atrayee Bhattacharya6Ayako Nakashoji7Mikita Suyama8Tomoyoshi Takenaka9Tomoharu Yoshizumi10Atsushi Osoegawa11Aaron N. Hata12Donald Kufe13Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Medicine, Massachusetts General Hospital, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDivision of Bioinformatics, Medical Institute of Bioregulation, Kyushu UniversityDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDivision of Bioinformatics, Medical Institute of Bioregulation, Kyushu UniversityDepartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Thoracic and Breast Surgery, Oita University Faculty of MedicineDepartment of Medicine, Massachusetts General Hospital, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolAbstract The APOBEC3 (A3) genes encoding cytidine deaminases evolved in mammals to restrict retroviral replication. The MUC1 gene appeared in mammals to protect barrier tissues from viral infections. There is no known involvement of the MUC1 encoded MUC1-C/M1C protein in the regulation of A3s. We found that induction of MUC1-C in NSCLC cells treated with EGFR inhibitors integrates activation of an inflammatory memory response with the type I interferon (IFN) STAT1/STAT2/IRF9 (U-ISGF3) pathway. In turn, MUC1-C drives expression of A3 genes by activating their U-ISGF3-stimulated response elements (ISREs). We also report that MUC1-C-mediated induction of type II IFN STAT1 homodimer (U-GAF) complexes and the gamma-associated signaling (GAS) pathway drives human endogenous retrovirus HERV-K102/K108 expression. Our results in NSCLC cell line and patient-derived models further demonstrate that MUC1-C activates A3 and HERV-K expression by a common MUC1-C→STAT1 auto-inductive pathway. These previously unrecognized findings demonstrate that a MUC1-C-driven inflammatory pathway coordinates activation of APOBEC3 and HERV-K expression.https://doi.org/10.1038/s41420-025-02673-9 |
| spellingShingle | Naoki Haratake Shinkichi Takamori Hideko Isozaki Keisuke Shigeta Chie Kikutake Hiroki Ozawa Atrayee Bhattacharya Ayako Nakashoji Mikita Suyama Tomoyoshi Takenaka Tomoharu Yoshizumi Atsushi Osoegawa Aaron N. Hata Donald Kufe Activation of APOBEC3 cytidine deaminases and endogenous retroviruses is integrated by MUC1-C in NSCLC cells Cell Death Discovery |
| title | Activation of APOBEC3 cytidine deaminases and endogenous retroviruses is integrated by MUC1-C in NSCLC cells |
| title_full | Activation of APOBEC3 cytidine deaminases and endogenous retroviruses is integrated by MUC1-C in NSCLC cells |
| title_fullStr | Activation of APOBEC3 cytidine deaminases and endogenous retroviruses is integrated by MUC1-C in NSCLC cells |
| title_full_unstemmed | Activation of APOBEC3 cytidine deaminases and endogenous retroviruses is integrated by MUC1-C in NSCLC cells |
| title_short | Activation of APOBEC3 cytidine deaminases and endogenous retroviruses is integrated by MUC1-C in NSCLC cells |
| title_sort | activation of apobec3 cytidine deaminases and endogenous retroviruses is integrated by muc1 c in nsclc cells |
| url | https://doi.org/10.1038/s41420-025-02673-9 |
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