Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial Control
Emerin is the inner nuclear membrane protein involved in maintaining the mechanical integrity of the nuclear membrane. Mutations in EMD encoding emerin cause Emery–Dreifuss muscular dystrophy (EDMD). Evidence is accumulating that emerin regulation of specific gene expression is associated with this...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/13/6669 |
| _version_ | 1797529199993421824 |
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| author | Byongsun Lee Seungjae Lee Younggwang Lee Yongjin Park Jaekyung Shim |
| author_facet | Byongsun Lee Seungjae Lee Younggwang Lee Yongjin Park Jaekyung Shim |
| author_sort | Byongsun Lee |
| collection | DOAJ |
| description | Emerin is the inner nuclear membrane protein involved in maintaining the mechanical integrity of the nuclear membrane. Mutations in EMD encoding emerin cause Emery–Dreifuss muscular dystrophy (EDMD). Evidence is accumulating that emerin regulation of specific gene expression is associated with this disease, but the exact function of emerin has not been fully elucidated. Here, we show that emerin downregulates Signal transducer and activators of transcription 3 (STAT3) signaling, activated exclusively by Janus kinase (JAK). Deletion mutation experiments show that the lamin-binding domain of emerin is essential for the inhibition of STAT3 signaling. Emerin interacts directly and co-localizes with STAT3 in the nuclear membrane. Emerin knockdown induces STAT3 target genes <i>Bcl2</i> and <i>Survivin</i> to increase cell survival signals and suppress hydrogen peroxide-induced cell death in HeLa cells. Specifically, downregulation of BAF or lamin A/C increases STAT3 signaling, suggesting that correct-localized emerin, by assembling with BAF and lamin A/C, acts as an intrinsic inhibitor against STAT3 signaling. In C2C12 cells, emerin knockdown induces STAT3 target gene, Pax7, and activated abnormal myoblast proliferation associated with muscle wasting in skeletal muscle homeostasis. Our results indicate that emerin downregulates STAT3 signaling by inducing retention of STAT3 and delaying STAT3 signaling in the nuclear membrane. This mechanism provides clues to the etiology of emerin-related muscular dystrophy and may be a new therapeutic target for treatment. |
| first_indexed | 2024-03-10T10:10:23Z |
| format | Article |
| id | doaj.art-15388996670d4077b15e0553d6d5f6cb |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T10:10:23Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-15388996670d4077b15e0553d6d5f6cb2023-11-22T01:11:02ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012213666910.3390/ijms22136669Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial ControlByongsun Lee0Seungjae Lee1Younggwang Lee2Yongjin Park3Jaekyung Shim4Department of Bioresources Engineering, Sejong University, Seoul 05006, KoreaDepartment of Bioresources Engineering, Sejong University, Seoul 05006, KoreaDepartment of Bioresources Engineering, Sejong University, Seoul 05006, KoreaDepartment of Bioresources Engineering, Sejong University, Seoul 05006, KoreaDepartment of Bioresources Engineering, Sejong University, Seoul 05006, KoreaEmerin is the inner nuclear membrane protein involved in maintaining the mechanical integrity of the nuclear membrane. Mutations in EMD encoding emerin cause Emery–Dreifuss muscular dystrophy (EDMD). Evidence is accumulating that emerin regulation of specific gene expression is associated with this disease, but the exact function of emerin has not been fully elucidated. Here, we show that emerin downregulates Signal transducer and activators of transcription 3 (STAT3) signaling, activated exclusively by Janus kinase (JAK). Deletion mutation experiments show that the lamin-binding domain of emerin is essential for the inhibition of STAT3 signaling. Emerin interacts directly and co-localizes with STAT3 in the nuclear membrane. Emerin knockdown induces STAT3 target genes <i>Bcl2</i> and <i>Survivin</i> to increase cell survival signals and suppress hydrogen peroxide-induced cell death in HeLa cells. Specifically, downregulation of BAF or lamin A/C increases STAT3 signaling, suggesting that correct-localized emerin, by assembling with BAF and lamin A/C, acts as an intrinsic inhibitor against STAT3 signaling. In C2C12 cells, emerin knockdown induces STAT3 target gene, Pax7, and activated abnormal myoblast proliferation associated with muscle wasting in skeletal muscle homeostasis. Our results indicate that emerin downregulates STAT3 signaling by inducing retention of STAT3 and delaying STAT3 signaling in the nuclear membrane. This mechanism provides clues to the etiology of emerin-related muscular dystrophy and may be a new therapeutic target for treatment.https://www.mdpi.com/1422-0067/22/13/6669JAKSTAT3emerinmuscular dystrophy |
| spellingShingle | Byongsun Lee Seungjae Lee Younggwang Lee Yongjin Park Jaekyung Shim Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial Control International Journal of Molecular Sciences JAK STAT3 emerin muscular dystrophy |
| title | Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial Control |
| title_full | Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial Control |
| title_fullStr | Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial Control |
| title_full_unstemmed | Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial Control |
| title_short | Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial Control |
| title_sort | emerin represses stat3 signaling through nuclear membrane based spatial control |
| topic | JAK STAT3 emerin muscular dystrophy |
| url | https://www.mdpi.com/1422-0067/22/13/6669 |
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