Multiple Protein Domains Contribute to Nuclear Import and Cell Toxicity of DUX4, a Candidate Pathogenic Protein for Facioscapulohumeral Muscular Dystrophy

EDGARDO DANIEL CORONA; DANIELA KARINA JACQUELIN; LAURA VIRGINIA GATICA; ALBERTO LUIS ROSA

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2013 vol. 8 p. 75614 - 75614

UX4 (Double Homeobox Protein 4) is a nuclear transcription factor encoded at each D4Z4 unit of a tandem-repeat array at human chromosome 4q35. DUX4 constitutes a major candidate pathogenic protein for facioscapulohumeral muscular dystrophy (FSHD), the third most common form of inherited myopathy. A low-level expression of DUX4 compromises cell differentiation in myoblasts and its overexpression induces apoptosis in cultured cells and living organisms. In this work we explore potential molecular determinants of DUX4 mediating nuclear import and cell toxicity. Deletion of the hypothetical monopartite nuclear localization sequences RRRR23, RRKR98 and RRAR148 (i.e. NLS1, NLS2 and NLS3, respectively) only partially delocalizes DUX4 from the cell nuclei. Nuclear entrance guided by NLS1, NLS2 and NLS3 does not follow the classical nuclear import pathway mediated by a/b importins. NLS and homeodomain mutants from DUX4 are dramatically less cell-toxic than the wild type molecule, independently