title: Ubiquitin conjugating enzyme E2-N and sequestosome-1 (p62) are components of the ubiquitination process mediated by the malin-laforin E3-ubiquitin ligase complex.
abstract: Lafora disease (LD, OMIM254780, ORPHA501) is a rare neurodegenerative form of epilepsy related to mutations in two proteins: laforin, a dual specificity phosphatase, and malin, an E3-ubiquitin ligase. Both proteins form a functional complex, where laforin recruits specific substrates to be ubiquitinated by malin. However, little is known about the mechanism driving malin-laforin mediated ubiquitination of its substrates. In this work we present evidence indicating that the malin-laforin complex interacts physically and functionally with the ubiquitin conjugating enzyme E2-N (UBE2N). This binding determines the topology of the chains that the complex is able to promote in the corresponding substrates (mainly K63-linked polyubiquitin chains). In addition, we demonstrate that the malin-laforin complex interacts with the selective autophagy adaptor sequestosome-1 (p62). Binding of p62 to the malin-laforin complex allows its recognition by LC3, a component of the autophagosomal membrane. In addition, p62 enhances the ubiquitinating activity of the malin-laforin E3-ubiquitin ligase complex. These data enrich our knowledge on the mechanism of action of the malin-laforin complex as an E3-ubiquitin ligase and reinforces the role of this complex in targeting substrates toward the autophagy pathway.
authors.affiliation: Instituto de Biomedicina de Valencia, CSIC and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010 Valencia, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Sánchez-Martín
authors.affiliation: Dept. Physiology, School of Medicine and Dentistry, University of Valencia and FIHCUV-INCLIVA, Valencia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Romá-Mateo
authors.affiliation: Instituto de Biomedicina de Valencia, CSIC and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010 Valencia, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Viana
authors.affiliation: Instituto de Biomedicina de Valencia, CSIC and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010 Valencia, Spain. Electronic address: sanz@ibv.csic.es.
authors.forename: Pascual
authors.initials: P
authors.lastname: Sanz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D001343:Autophagy; D002352:Carrier Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D010588:Phagosomes / Q000378:metabolism; D011485:Protein Binding; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D044763:Ubiquitin-Conjugating Enzymes / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes; C478960:NHLRC1 protein, human; D044767:Ubiquitin-Protein Ligases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human
keywords: Autophagosome; E2-conjugase; E3-ubiquitin ligase; LC3; Laforin; Malin; UBE2N; Ubiquitination; p62 (SQSTM1)