DI-UMONS : Dépôt institutionnel de l’université de Mons

Recherche transversale
(titres de publication, de périodique et noms de colloque inclus)
2018-06-08 - Colloque/Présentation - poster - Anglais - 1 page(s)

Claus Clothilde , Salvin Moriya, Tayri Tamar, Ansseau Eugénie , Decleves Anne-Emilie , Wilton Steve, Kalisman Nir, Coppée Frédérique , "Direct interaction of DUX4/4c with the multifunctional protein C1QBP" in FSH International Research Congress, Las Vegas, USA, 2018

  • Codes CREF : Biochimie (DI3112), Biologie moléculaire (DI3111)
  • Unités de recherche UMONS : Biochimie métabolique et moléculaire (M122)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)
  • Centres UMONS : Centre de Recherche UMONS-Ambroise Paré (UMHAP)
Texte intégral :

Abstract(s) :

(Anglais) Clothilde Claus1, Moriya Slavin2, Tamar Tayri2, Eugénie Ansseau1, Anne-Emilie Declèves1, Steve Wilton3, Nir Kalisman2 and Frédérique Coppée1 1 Laboratory of Molecular Biology, Research Institute for Health Sciences and Technology, University of Mons, Belgium 2 Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Israel 3 Laboratory of Molecular Genetics, Centre for Comparative Genomics, Murdoch University, Western Australia DUX4 (DoUble homeoboX4), the FSHD causal gene, is a nuclear transcription factor. Its overexpression in myoblasts induces a cascade of gene expression that interferes with many pathways leading to typical FSHD features such as muscles wasting, inflammation, decreased innate immune response, and oxidative stress. However, other FSHD muscle cell features are not yet understood such as its clusters of myonuclei and cytoskeletal defects. DUX4c, a DUX4 homologue, is identical in the first 342 amino acid residues but is 50-residues shorter than DUX4. Interestingly, DUX4c is expressed at low level in healthy muscles but greatly increased in FSHD ones. It could act as an FSHD modifier gene. FSHD is a gain-of-function pathology. DUX4 expression is stochastic, has irreversible downstream effects and a short half-live. Therefore, the time window to target it is difficult. Current therapeutic developments focus on the inhibition of its expression or activity. However, in view of DUX4 pleiotropic effects, combinatory treatments acting at different level (similarly to tri-therapy in AIDS) might overcome the development or progression of the disease. Therefore, a better understanding of the impact of DUX4/4c overexpression, in healthy and pathological muscles is needed. For this purpose, our lab in collaboration with S. Harper’s group, searched to identify DUX4/4c protein partners using several methods as well as different cell types, and surprisingly found a lot of RNA-binding proteins and also cytoplasmic proteins (Ansseau et al., 2016). To further confirm the specificity of these interactions, we now used cross-linking and mass-spectrometry to covalently capture DUX4/4c bound to its protein partners. This new method also allows to define the quaternary structures of these protein complexes. Our first results are in keeping with our previous published data. Moreover, we found that C1QBP (complement component 1Q subcomponent-binding protein), a multifunctional and multicompartmental protein (we already validated as a DUX4 partner, Ansseau et al. 2016), interacts directly with DUX4c. Here, cross-links between C1QBP and DUX4c are found in two regions that are identical in DUX4. In addition, the observed C1QBP internal cross-links are in agreement with its known X-ray structure. C1QBP is involved in apoptosis, innate immunity, mRNA processing, mRNA splicing, ribosome biogenesis and transcriptional regulation. As we postulate that DUX4 interferes with a normal role of DUX4c in skeletal muscle, a clear knowledge of the DUX4 or DUX4c interactome will help to find new perspectives for therapeutic strategies for FSHD without inhibition of muscle functions: either by the development of interfering molecules that suppress/decrease the DUX4 interactions involved in toxic pathways or by the use/ development of molecules specifically targeting DUX4-downstream pathways or combined therapies. Acknowledgement: CC held fellowships from FSHD Global Research Foundation (Australia), Amis FSH (France), ABMM (Belgium) and EA post-doctoral held fellowships from FSH Society (USA). We thank Prof. Alexandra Belayew for her constant support.