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The Prader-Willi syndrome proteins MAGEL2 and necdin regulate leptin receptor cell surface abundance through ubiquitination pathways

(2017) HUMAN MOLECULAR GENETICS. 26(21). p.4215-4230
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Abstract
In Prader-Willi syndrome (PWS), obesity is caused by the disruption of appetite-controlling pathways in the brain. Two PWS candidate genes encode MAGEL2 and necdin, related melanoma antigen proteins that assemble into ubiquitination complexes. Mice lacking Magel2 are obese and lack leptin sensitivity in hypothalamic pro-opiomelanocortin neurons, suggesting dysregulation of leptin receptor (LepR) activity. Hypothalamus from Magel2-null mice had less LepR and altered levels of ubiquitin pathway proteins that regulate LepR processing (Rnf41, Usp8, and Stam1). MAGEL2 increased the cell surface abundance of LepR and decreased their degradation. LepR interacts with necdin, which interacts with MAGEL2, which complexes with RNF41 and USP8. Mutations in the MAGE homology domain of MAGEL2 suppress RNF41 stabilization and prevent the MAGEL2-mediated increase of cell surface LepR. Thus, MAGEL2 and necdin together control LepR sorting and degradation through a dynamic ubiquitin-dependent pathway. Loss of MAGEL2 and necdin may uncouple LepR from ubiquitination pathways, providing a cellular mechanism for obesity in PWS.
Keywords
P75 NEUROTROPHIN RECEPTOR, MOUSE MODEL, TRUNCATING MUTATIONS, LIGASE NRDP1, MICE LACKING, SCHAAF-YANG, GENE, OBESITY, DIFFERENTIATION, TRAFFICKING

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Citation

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MLA
Wijesuriya, Tishani Methsala, Leentje De Ceuninck, Delphine Masschaele, et al. “The Prader-Willi Syndrome Proteins MAGEL2 and Necdin Regulate Leptin Receptor Cell Surface Abundance Through Ubiquitination Pathways.” HUMAN MOLECULAR GENETICS 26.21 (2017): 4215–4230. Print.
APA
Wijesuriya, T. M., De Ceuninck, L., Masschaele, D., Sanderson, M. R., Carias, K. V., Tavernier, J., & Wevrick, R. (2017). The Prader-Willi syndrome proteins MAGEL2 and necdin regulate leptin receptor cell surface abundance through ubiquitination pathways. HUMAN MOLECULAR GENETICS, 26(21), 4215–4230.
Chicago author-date
Wijesuriya, Tishani Methsala, Leentje De Ceuninck, Delphine Masschaele, Matthea R Sanderson, Karin Vanessa Carias, Jan Tavernier, and Rachel Wevrick. 2017. “The Prader-Willi Syndrome Proteins MAGEL2 and Necdin Regulate Leptin Receptor Cell Surface Abundance Through Ubiquitination Pathways.” Human Molecular Genetics 26 (21): 4215–4230.
Chicago author-date (all authors)
Wijesuriya, Tishani Methsala, Leentje De Ceuninck, Delphine Masschaele, Matthea R Sanderson, Karin Vanessa Carias, Jan Tavernier, and Rachel Wevrick. 2017. “The Prader-Willi Syndrome Proteins MAGEL2 and Necdin Regulate Leptin Receptor Cell Surface Abundance Through Ubiquitination Pathways.” Human Molecular Genetics 26 (21): 4215–4230.
Vancouver
1.
Wijesuriya TM, De Ceuninck L, Masschaele D, Sanderson MR, Carias KV, Tavernier J, et al. The Prader-Willi syndrome proteins MAGEL2 and necdin regulate leptin receptor cell surface abundance through ubiquitination pathways. HUMAN MOLECULAR GENETICS. 2017;26(21):4215–30.
IEEE
[1]
T. M. Wijesuriya et al., “The Prader-Willi syndrome proteins MAGEL2 and necdin regulate leptin receptor cell surface abundance through ubiquitination pathways,” HUMAN MOLECULAR GENETICS, vol. 26, no. 21, pp. 4215–4230, 2017.
@article{8554660,
  abstract     = {In Prader-Willi syndrome (PWS), obesity is caused by the disruption of appetite-controlling pathways in the brain. Two PWS candidate genes encode MAGEL2 and necdin, related melanoma antigen proteins that assemble into ubiquitination complexes. Mice lacking Magel2 are obese and lack leptin sensitivity in hypothalamic pro-opiomelanocortin neurons, suggesting dysregulation of leptin receptor (LepR) activity. Hypothalamus from Magel2-null mice had less LepR and altered levels of ubiquitin pathway proteins that regulate LepR processing (Rnf41, Usp8, and Stam1). MAGEL2 increased the cell surface abundance of LepR and decreased their degradation. LepR interacts with necdin, which interacts with MAGEL2, which complexes with RNF41 and USP8. Mutations in the MAGE homology domain of MAGEL2 suppress RNF41 stabilization and prevent the MAGEL2-mediated increase of cell surface LepR. Thus, MAGEL2 and necdin together control LepR sorting and degradation through a dynamic ubiquitin-dependent pathway. Loss of MAGEL2 and necdin may uncouple LepR from ubiquitination pathways, providing a cellular mechanism for obesity in PWS.},
  author       = {Wijesuriya, Tishani Methsala and De Ceuninck, Leentje and Masschaele, Delphine and Sanderson, Matthea R and Carias, Karin Vanessa and Tavernier, Jan and Wevrick, Rachel},
  issn         = {0964-6906},
  journal      = {HUMAN MOLECULAR GENETICS},
  keywords     = {P75 NEUROTROPHIN RECEPTOR,MOUSE MODEL,TRUNCATING MUTATIONS,LIGASE NRDP1,MICE LACKING,SCHAAF-YANG,GENE,OBESITY,DIFFERENTIATION,TRAFFICKING},
  language     = {eng},
  number       = {21},
  pages        = {4215--4230},
  title        = {The Prader-Willi syndrome proteins MAGEL2 and necdin regulate leptin receptor cell surface abundance through ubiquitination pathways},
  url          = {http://dx.doi.org/10.1093/hmg/ddx311},
  volume       = {26},
  year         = {2017},
}

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