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 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 Bcl2 and Survivin 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.
['Lee|Byongsun|B|', 'Lee|Seungjae|S|', 'Lee|Younggwang|Y|', 'Park|Yongjin|Y|', 'Shim|Jaekyung|J|0000-0002-7643-9234']
D000072283:A549 Cells D002467:Cell Nucleus D002470:Cell Survival D005786:Gene Expression Regulation D006801:Humans D053612:Janus Kinases D008565:Membrane Proteins D018482:Muscle, Skeletal D009136:Muscular Dystrophies D009154:Mutation D009685:Nuclear Envelope D009687:Nuclear Proteins D011485:Protein Binding D050796:STAT3 Transcription Factor D015398:Signal Transduction D014157:Transcription Factors
emerin STAT3 muscular dystrophy JAK