The Emery–Dreifuss muscular dystrophy associated‐protein emerin is phosphorylated on serine 49 by protein kinase A

Roberts, Rhys; Sutherland-Smith, Andrew J.; Wheeler, Matthew; Jensen, Ole N.; Emerson, Lindsay J.; Spiliotis, Ioannis; Tate, Christopher G.; Kendrick‐Jones, John; Ellis, Juliet A.

doi:10.1111/j.1742-4658.2006.05464.x

Cited by 22 publications

(30 citation statements)

References 44 publications

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“…Consequently, the opsin tag with its N-glycosylation site must have reached the microsomal lumen, confirming membrane insertion of the tail-anchored protein. Addition of lambda-phosphatase largely abolished the smear of higher molecular mass forms, in agreement with earlier observations that emerin can be phosphorylated (Ellis et al, 1998;Leach et al, 2007;Roberts et al, 2006). TRC40-dependent membrane integration of tail-anchored proteins is an active, ATP-dependent process (Favaloro et al, 2008(Favaloro et al, , 2010Stefanovic and Hegde, 2007).…”

Section: Post-translational Membrane Integration Of Emerin By the Trcsupporting

confidence: 75%

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

Pfaff

Rivera‐Monroy

Jamieson

et al. 2016

Journal of Cell Science

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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 EmeryDreifuss 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 INMtargeting 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.

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Section: Post-translational Membrane Integration Of Emerin By the Trcsupporting

confidence: 75%

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

Pfaff

Rivera‐Monroy

Jamieson

et al. 2016

Journal of Cell Science

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“…We predict that post-translational modification of Lmo7 or emerin, or both, increases their affinity for one another. Emerin contains four serine, one threonine and 13 tyrosine residues that are phosphorylated in vitro and in vivo (Amanchy et al, 2005;Brill et al, 2004;Hirano et al, 2005;Roberts et al, 2006;Schlosser et al, 2006), many of which regulate binding to its partners (Hirano et al, 2005;Roberts et al, 2006;Tifft et al, 2009). However, it is not well documented how emerin phosphorylation changes during myogenic differentiation.…”

Section: Emerin Regulates Lmo7 Binding To and Activation Of Myogenic mentioning

confidence: 99%

Emerin inhibits Lmo7 binding to thePax3andMyoDpromoters and expression of myoblast proliferation genes

Dedeić

Cetera

Cohen

et al. 2011

Journal of Cell Science

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SummaryX-linked Emery-Dreifuss muscular dystrophy (X-EDMD) is caused by mutations in the inner nuclear membrane protein emerin. Previous studies have shown that emerin binds to and inhibits the activity of LIM domain only 7 (Lmo7), a transcription factor that regulates the expression of genes implicated in X-EDMD. Here, we analyzed Lmo7 function in C2C12 myoblast differentiation and its regulation by emerin. We found that Lmo7 was required for proper myoblast differentiation. Lmo7-downregulated myoblasts exhibited reduced expression of Pax3, Pax7, Myf5 and MyoD, whereas overexpression of GFP-Lmo7 increased the expression of MyoD and Myf5. Upon myotube formation, Lmo7 shuttled from the nucleus to the cytoplasm, concomitant with reduced expression of MyoD, Pax3 and Myf5. Importantly, we show that Lmo7 bound the Pax3, MyoD and Myf5 promoters both in C2C12 myoblasts and in vitro. Because emerin inhibited Lmo7 activity, we tested whether emerin competed with the MyoD promoter for binding to Lmo7 or whether emerin sequestered promoter-bound Lmo7 to the nuclear periphery. Supporting the competition model, emerin binding to Lmo7 inhibited Lmo7 binding to and activation of the MyoD and Pax3 promoters. These findings support the hypothesis that the functional interaction between emerin and Lmo7 is crucial for temporally regulating the expression of key myogenic differentiation genes.

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“…It has been previously demonstrated that emerin is phosphorylated; hence, the higher molecular weight isoform we detected in fibroblasts Y259X/Y259X may be phosphorylated [20][21][22][23][24]. To assess whether the protein with an apparent molecular mass of 36 kDa recognized by antiemerin antibodies was a phosphorylated form of emerin, we treated fibroblasts Y259X/Y259X with the phosphatase inhibitor okadaic acid (OA).…”

Section: Effect Of Lack Of A-type Lamins In Cells Homozygous For the mentioning

confidence: 99%

Proteasome-mediated degradation of integral inner nuclear membrane protein emerin in fibroblasts lacking A-type lamins

Muchir

Massart

Engelen

et al. 2006

Biochemical and Biophysical Research Communications

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We previously identified and characterized a homozygous LMNA nonsense mutation leading to the absence of A-type lamins in a premature neonate who died at birth. We show here that the absence of A-type lamins is due to degradation of the aberrant mRNA transcript with a premature termination codon. In cultured fibroblasts from the subject with the homozygous LMNA nonsense mutation, there was a decreased steady-state expression of the integral inner nuclear membrane proteins emerin and nesprin-1α associated with their mislocalization to the bulk endoplasmic reticulum and a hyperphosphorylation of emerin. To determine if decreased emerin expression occurred posttranslationally, we treated cells with a selective proteasome inhibitor and observed an increase in expression. Our results show that mislocalization of integral inner nuclear membrane proteins to the endoplasmic reticulum in human cells lacking A-type lamins leads to their degradation and provides the first evidence that their degradation is mediated by the proteasome. KeywordsNuclear envelope; Lamin; Emerin; Nesprin; Proteasome; Muscular dystrophy Lamins are intermediate filament proteins that form the nuclear lamina, a fibrous meshwork underlying the inner nuclear membrane of higher eukaryotic cells [1]. In human, two types of lamins are expressed in somatic cells according to their sequences and biochemical properties, A-type and B-type. Lamins A and C, encoded by the LMNA gene, are the predominant A-type lamins in mammalian somatic cells and arise from alternative RNA splicing. Two genes, LMNB1 and LMNB2, respectively, encode the somatic mammalian B-type lamins B1 and B2 [1]. While lamins B1 and B2 are expressed in most of all somatic cells, the expression of Atype lamins is developmentally regulated and generally restricted to differentiated cells [2,3]. The nuclear lamina is attached to the inner nuclear membrane via interactions with integral proteins, among them emerin, nesprin-1α, LBR, and LAPs [4]. Lamins A and C also interact

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The Emery–Dreifuss muscular dystrophy associated‐protein emerin is phosphorylated on serine 49 by protein kinase A

Cited by 22 publications

References 44 publications

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

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

Emerin inhibits Lmo7 binding to thePax3andMyoDpromoters and expression of myoblast proliferation genes

Proteasome-mediated degradation of integral inner nuclear membrane protein emerin in fibroblasts lacking A-type lamins

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