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Profiling of the Muscle-Specific Dystroglycan Complexome Identifies Novel Muscular Dystrophy Factors

2019; RELX Group (Netherlands); Linguagem: Inglês

10.2139/ssrn.3362387

1556-5068

Mariya M. Kucherenko, Yuanbin Xie, Andriy S. Yatsenko, Dina Aweida, Henning Urlaub, Shenhav Cohen, Halyna R. Shcherbata,

Calpain Protease Function and Regulation

Dystroglycanopathies are a group of inherited disorders characterized by vast clinical and genetic heterogeneity caused by abnormal functioning of the ECM receptor Dystroglycan (Dg). Remarkably, among many cases of diagnosed dystroglycanopathies, only a small fraction can be directly linked to mutations in Dg or its regulatory enzymes, implying the involvement of other, not yet characterized Dg-regulating factors. To identify new players contributing to dystroglycanopathies, we used Drosophila as a genetic muscular dystrophy model. We analyzed the muscle-specific Dg complexome and identified novel Dg interactors, the majority of which are conserved and have human disease-associated homologs. We discovered that components of the Hippo pathway interact physically and genetically with Dg in adult muscles. Dg associates with the WW domain-containing proteins, Kibra and Yorkie, controlling muscle size and integrity. We propose that Dg acts as a transmembrane Hippo signaling receptor that transmits extracellular information to intracellular signaling cascades, regulating muscle gene expression.