Abstract
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.
Highlights
We investigated the involvement of emerin in Signal transducer and activators of transcription 3 (STAT3) signaling in the same manner as a previously reported human transcription factor profiling assay that measures the expression levels of genes using Quantitative RT-PCR (qRT-PCR) [15]
We found that the expression of the STAT family was significantly reduced by emerin, and MyoD and Myf5, which are related to muscle development, were reduced
We found that emerin plays a role in the transcriptional suppression of many genes, including those of the Notch, Wnt, and STAT signaling pathways (Figure 1A,B and Supplementary Table S1)
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The nuclear lamina provides mechanical assistance to the nucleus and a protein network that contributes to DNA replication, gene regulation, and genome stability [1,2]. The nuclear lamina proteins scaffold hundreds of proteins, including the LAP2-emerinMAN1-domain (LEM-D) protein family in the inner nuclear membrane [3,4]. Multiple human diseases are caused by the loss of individual nuclear lamina proteins, highlighting the importance of this network [2,5]. Emerin was initially identified as a 35 kDa inner nuclear transmembrane protein that interacts with structural proteins including lamin
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
