A MAGEL2-deubiquitinase complex modulates the ubiquitination of circadian rhythm protein CRY1.

K Vanessa Carias,Matthea R Sanderson,Mercedes Zoeteman,Jocelyn M Bischof,Rachel Wevrick,Abigail Seewald,Henrik Oster

doi:10.1371/journal.pone.0230874

Abstract

MAGEL2 encodes the L2 member of the MAGE (melanoma antigen) protein family. Protein truncating mutations in MAGEL2 cause Schaaf-Yang syndrome, and MAGEL2 is one of a small set of genes deleted in Prader-Willi syndrome. Excessive daytime sleepiness, night-time or early morning waking, and narcoleptic symptoms are seen in people with Prader-Willi syndrome and Schaaf-Yang syndrome, while mice carrying a gene-targeted Magel2 deletion have disrupted circadian rhythms. These phenotypes suggest that MAGEL2 is important for the robustness of the circadian rhythm. However, a cellular role for MAGEL2 has yet to be elucidated. MAGEL2 influences the ubiquitination of substrate proteins to target them for further modification or to alter their stability through proteasomal degradation pathways. Here, we characterized relationships among MAGEL2 and proteins that regulate circadian rhythm. The effect of MAGEL2 on the key circadian rhythm protein cryptochrome 1 (CRY1) was assessed using in vivo proximity labelling (BioID), immunofluorescence microscopy and ubiquitination assays. We demonstrate that MAGEL2 modulates the ubiquitination of CRY1. Further studies will clarify the cellular role MAGEL2 normally plays in circadian rhythm, in part through ubiquitination and regulation of stability of the CRY1 protein.

Highlights

Prader-Willi Syndrome (PWS) is a genetic disorder of the nervous and endocrine systems characterized by developmental disabilities, hypotonia, hyperphagia, and obesity
We propose that disruption of circadian rhythm in people with Prader-Willi syndrome may be caused by MAGEL2-dependent deficiencies in the ubiquitin-dependent regulation of cryptochrome 1 (CRY1) levels
Magel2 is highly expressed in the hypothalamus, and most highly in the Regulation of circadian rhythm by MAGEL2 through ubiquitin-dependent processes paraventricular and suprachiasmatic nuclei of the hypothalamus (S1A and S1A’ Fig)

Summary

Introduction

Prader-Willi Syndrome (PWS) is a genetic disorder of the nervous and endocrine systems characterized by developmental disabilities, hypotonia, hyperphagia, and obesity. Sleep apnea (obstructive and central), poor responses to hypoxia and hypercapnia, night wakening and narcoleptic symptoms contribute to abnormal sleep structure in individuals with PWS [1]. Excessive daytime sleepiness affects 90–100% of adults with PWS, according to parental reports [2]. Obesity and excessive daytime sleepiness are caused by hypothalamic dysfunction [3]. Therapies for excessive daytime sleepiness in PWS are largely focussed on relief of symptoms. Modafinil was effective at reducing daytime sleepiness in an open label pilot study of children and adolescents with PWS, but has not yet been tested in a clinical trial setting [4]

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Results

Conclusion