Skeletal muscle-specific variant of nascent polypeptide associated complex alpha (skNAC): Implications for a specific role in mammalian myoblast differentiation

Berger, Felicitas; Berkholz, Janine; Breustedt, Theresia; Ploen, Daniela; Munz, Barbara

doi:10.1016/j.ejcb.2011.10.004

Cited by 14 publications

(19 citation statements)

References 18 publications

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“…This staining pattern was clearly different from that observed in untransfected cells or those transfected with a scrambled siRNA, in which the typical, homogeneously distributed spotty staining of newly forming sarcomeres was detected (Fig. 3D), and was reminiscent of the MyHC and a-sarcomeric actin staining patterns we had observed previously in myoblasts in which skNAC expression had been knocked down (Berger et al, 2012;Berkholz et al, 2013). The perturbed sarcomerogenesis we had seen previously in cells that had been transfected with siRNA against skNAC was dependent on an induction of calpain gene expression and calpain enzymatic activity (Berger et al, 2012).…”

Section: Inhibition Of Nse2 Expression Influences Expression Of Genesmentioning

confidence: 68%

“…This was most probably due to defects in myofibrillogenesis and/or sarcomerogenesis; embryos in which skNAC expression had been knocked down showed irregular distribution of actin and myosin filaments and no formation of well-structured sarcomeres. Correspondingly, we have recently demonstrated defective sarcomerogenesis in murine C2C12 myoblasts after skNAC depletion using a small interfering (si)RNA-mediated approach (Berger et al, 2012;Berkholz et al, 2013). These data implicate skNAC in the regulation of sarcomere formation.…”

Section: Introductionmentioning

confidence: 81%

“…3D), and was reminiscent of the MyHC and a-sarcomeric actin staining patterns we had observed previously in myoblasts in which skNAC expression had been knocked down (Berger et al, 2012;Berkholz et al, 2013). The perturbed sarcomerogenesis we had seen previously in cells that had been transfected with siRNA against skNAC was dependent on an induction of calpain gene expression and calpain enzymatic activity (Berger et al, 2012). Calpains are a family of Ca 2+ -dependent proteases with a proven role in the regulation of skeletal and heart muscle homeostasis (Sorimachi and Ono, 2012).…”

Section: Inhibition Of Nse2 Expression Influences Expression Of Genesmentioning

confidence: 96%

“…skNAC and its known binding partner Smyd1 have been demonstrated to regulate myogenesis, specifically skeletal myoblast migration and sarcomerogenesis (Tan et al, 2006;Li et al, 2009, Li et al, 2011Just et al, 2011;Berger et al, 2012, Berkholz et al, 2013Li et al, 2013). Because both proteins undergo nuclear-to-cytoplasmic translocation during myogenesis (Sims et al, 2002), it is probable that they fulfill specific functions in both cellular compartments; in early myogenesis, they might act as transcriptional modulators, presumably through two specific domains within the Smyd1 protein -the so-called SET domain, which is a histone methyltransferase moiety, and the MYND domain, which is a potential recruiter of HDACs.…”

Section: Discussionmentioning

confidence: 99%

“…3C). Because we had recently demonstrated a role for skNAC in the control of sarcomerogenesis in mammalian cells (Berger et al, 2012;Berkholz et al, 2013), we hypothesized Fig. 3.…”

Section: Inhibition Of Nse2 Expression Influences Expression Of Genesmentioning

confidence: 99%

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The E3 SUMO ligase Nse2 regulates sumoylation and nuclear-to-cytoplasmic translocation of skNAC-Smyd1 in myogenesis

Berkholz

Michalick

Munz³

2014

Journal of Cell Science

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Skeletal and heart muscle-specific variant of the a subunit of nascent polypeptide associated complex (skNAC; encoded by NACA) is exclusively found in striated muscle cells. Its function, however, is largely unknown. Previous reports have demonstrated that skNAC binds to m-Bop/Smyd1, a multi-functional protein that regulates myogenesis both through the control of transcription and the modulation of sarcomerogenesis, and that both proteins undergo nuclear-to-cytoplasmic translocation at the later stages of myogenic differentiation. Here, we show that skNAC binds to the E3 SUMO ligase mammalian Mms21/Nse2 and that knockdown of Nse2 expression inhibits specific aspects of myogenic differentiation, accompanied by a partial blockade of the nuclearto-cytoplasmic translocation of the skNAC-Smyd1 complex, retention of the complex in promyelocytic leukemia (PML)-like nuclear bodies and disturbed sarcomerogenesis. In addition, we show that the skNAC interaction partner Smyd1 contains a putative sumoylation motif and is sumoylated in muscle cells, with depletion of Mms21/Nse2 leading to reduced concentrations of sumoylated Smyd1. Taken together, our data suggest that the function, specifically the balance between the nuclear and cytosolic roles, of the skNAC-Smyd1 complex might be regulated by sumoylation.

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Section: Inhibition Of Nse2 Expression Influences Expression Of Genesmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 81%

Section: Inhibition Of Nse2 Expression Influences Expression Of Genesmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

“…3C). Because we had recently demonstrated a role for skNAC in the control of sarcomerogenesis in mammalian cells (Berger et al, 2012;Berkholz et al, 2013), we hypothesized Fig. 3.…”

Section: Inhibition Of Nse2 Expression Influences Expression Of Genesmentioning

confidence: 99%

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The E3 SUMO ligase Nse2 regulates sumoylation and nuclear-to-cytoplasmic translocation of skNAC-Smyd1 in myogenesis

Berkholz

Michalick

Munz³

2014

Journal of Cell Science

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SMYD Proteins: Key Regulators in Skeletal and Cardiac Muscle Development and Function

Tan

Zhang

2014

The Anatomical Record

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Muscle fibers are composed of myofibrils, one of the most highly ordered macromolecular assemblies in cells. Recent studies demonstrate that members of the Smyd family play critical roles in myofibril assembly of skeletal and cardiac muscle during development. The Smyd family consists of five members including Smyd1, Smyd2, Smyd3, Smyd4, and Smyd5. They share two highly conserved structural and functional domains, namely the SET and MYND domains involved in lysine methylation and protein-protein interaction, respectively. Smyd1 is specifically expressed in muscle cells under the regulation of myogenic transcriptional factors of the MyoD and Mef2 families and the serum responsive factor. Loss of function studies reveal that Smyd1 is required for cardiomyogenesis and sarcomere assembly in skeletal and cardiac muscles. Smyd2, on another hand, is dispensable for heart development in mice. However, Smyd2 appears to play a role in myofilament organization in both skeletal and cardiac muscles via Hsp90 methylation. A Drosophila Smyd4 homologue is a muscle-specific transcriptional modulator involved in the development or function of adult muscle. The molecular mechanisms by which Smyd family proteins function in muscle cells are not well understood. It has been suggested that members of the Smyd family may use multiple mechanisms to control muscle development and cell differentiation, including transcriptional regulation, epigenetic regulation via histone methylation, and methylation of proteins other than histones, such as molecular chaperone Hsp90.

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Overexpression of the skNAC gene in human rhabdomyosarcoma cells enhances their differentiation potential and inhibits tumor cell growth and spreading

Berkholz

Kuzyniak

Hoepfner

et al. 2014

Clin Exp Metastasis

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Skeletal and heart muscle-specific variant of the alpha subunit of nascent polypeptide complex (skNAC) is exclusively present in striated muscle cells. During skeletal muscle cell differentiation, skNAC expression is strongly induced, suggesting that the protein might be a regulator of the differentiation process. Rhabdomyosarcoma is a tumor of skeletal muscle origin. Since there is a strong inverse correlation between rhabdomyosarcoma cell differentiation status and metastatic potential, we analyzed skNAC expression patterns in a set of rhabdomyosarcoma cell lines: Whereas RD/12 and RD/18 cells showed a marked induction of skNAC gene expression upon the induction of differentiation-similarly as the one seen in nontransformed myoblasts-skNAC was not induced in CCA or Rh30 cells. Overexpressing skNAC in CCA and Rh30 cells led to a reduction in cell cycle progression and cell proliferation accompanied by an upregulation of specific myogenic differentiation markers, such as Myogenin or Myosin Heavy Chain. Furthermore, in contrast to vector-transfected controls, a high percentage of the cells formed long, Myosin Heavy Chain-positive, multinucleate myotubes. Consistently, soft agar assays revealed a drop in the metastatic potential of skNAC-overexpressing cells. Taken together, these data indicate that reconstitution of skNAC expression can enhance the differentiation potential of rhabdomyosarcoma cells and reduces their metastatic potential, a finding which might have important therapeutic implications.

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Skeletal muscle-specific variant of nascent polypeptide associated complex alpha (skNAC): Implications for a specific role in mammalian myoblast differentiation

Cited by 14 publications

References 18 publications

The E3 SUMO ligase Nse2 regulates sumoylation and nuclear-to-cytoplasmic translocation of skNAC-Smyd1 in myogenesis

The E3 SUMO ligase Nse2 regulates sumoylation and nuclear-to-cytoplasmic translocation of skNAC-Smyd1 in myogenesis

SMYD Proteins: Key Regulators in Skeletal and Cardiac Muscle Development and Function

Overexpression of the skNAC gene in human rhabdomyosarcoma cells enhances their differentiation potential and inhibits tumor cell growth and spreading

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