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J Cell Sci. 2016 Feb 1;129(3):502-16. doi: 10.1242/jcs.179333. Epub 2015 Dec 16.

Emery-Dreifuss muscular dystrophy mutations impair TRC40-mediated targeting of emerin to the inner nuclear membrane.

Author information

1
Department of Molecular Biology, Faculty of Medicine, Georg-August-University, GZMB, Humboldtallee 23, Göttingen 37073, Germany.
2
Department of Molecular Biology, Faculty of Medicine, Georg-August-University, GZMB, Humboldtallee 23, Göttingen 37073, Germany Max-Planck Institute for Biophysical Chemistry, Göttingen 37077, Germany blanche.schwappach@med.uni-goettingen.de rkehlen@gwdg.de.
3
Department of Molecular Biology, Faculty of Medicine, Georg-August-University, GZMB, Humboldtallee 23, Göttingen 37073, Germany blanche.schwappach@med.uni-goettingen.de rkehlen@gwdg.de.

Abstract

Emerin is a tail-anchored protein that is found predominantly at the inner nuclear membrane (INM), where it associates with components of the nuclear lamina. Mutations in the emerin gene cause Emery-Dreifuss muscular dystrophy (EDMD), an X-linked recessive disease. Here, we report that the TRC40/GET pathway for post-translational insertion of tail-anchored proteins into membranes is involved in emerin-trafficking. Using proximity ligation assays, we show that emerin interacts with TRC40 in situ. Emerin expressed in bacteria or in a cell-free lysate was inserted into microsomal membranes in an ATP- and TRC40-dependent manner. Dominant-negative fragments of the TRC40-receptor proteins WRB and CAML (also known as CAMLG) inhibited membrane insertion. A rapamycin-based dimerization assay revealed correct transport of wild-type emerin to the INM, whereas TRC40-binding, membrane integration and INM-targeting of emerin mutant proteins that occur in EDMD was disturbed. Our results suggest that the mode of membrane integration contributes to correct targeting of emerin to the INM.

KEYWORDS:

CAML; Emerin; Inner nuclear membrane; TRC40; Tail-anchored protein; WRB

PMID:
26675233
DOI:
10.1242/jcs.179333
[Indexed for MEDLINE]
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