title: Lafora disease E3 ubiquitin ligase malin is recruited to the processing bodies and regulates the microRNA-mediated gene silencing process via the decapping enzyme Dcp1a.
abstract: Intracellular transport, processing and stability of mRNA play critical roles in the functional physiology of the cell and defects in these processes are thought to underlie the pathogenesis in a number of neurodegenerative disorders. One of the cellular sites that regulate the mRNA half-life is the processing bodies, the dynamic cytoplasmic structures that represent the non-translating mRNA and the ribonucleoprotein complex that also control the decapping and translation of mRNA. In the present study we explored the possible role of malin E3 ubiquitin ligase in the mRNA decay pathway via the processing bodies. Defects in malin are associated with Lafora disease (LD)-a neurodegenerative disorder characterized by myoclonus seizures. We show here that malin is recruited to the processing bodies and that malin regulates the recruitment of mRNA decapping enzyme Dcp1a by promoting its degradation via the ubiquitin proteasome system. Depletion of malin results in elevated levels of Dcp1a and an altered microRNA-mediated gene silencing activity. Our study suggests that malin is one of the critical regulators of processing bodies and that defects in the mRNA processing might underlie some of the disease symptoms in LD.
authors.affiliation: Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
authors.forename: Sweta
authors.initials: S
authors.lastname: Singh
authors.forename: Pankaj Kumar
authors.initials: PK
authors.lastname: Singh
authors.forename: Pratibha
authors.initials: P
authors.lastname: Bhadauriya
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ganesh
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D020192:Lafora Disease / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D025941:Protein Interaction Mapping; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D035683:MicroRNAs; D046912:Multiprotein Complexes; D015534:Trans-Activators; C478960:NHLRC1 protein, human; C572596:NHLRC1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D004722:Endoribonucleases; C466279:DCP1A protein, human
keywords: RNA granules; epilepsy; mRNA dysregulation; neurodegenerative disorder; neuronal processing bodies; post-translational modification; stress response