Nature of the nuclear inclusions formed by PQBP1, a protein linked to neurodegenerative polyglutamine diseases.
PQBP1, for polyglutamine tract-binding protein-1, has been linked to progressive neurodegenerative diseases, such as spinocerebellar ataxia, that are caused by the expansion of a polyglutamine repeat in a key regulatory protein. The overexpression of PQBP1 results in the formation of nuclear inclusions, reminiscent of the protein aggregates that are detected in polyglutamine diseases. We show here that the occurrence of PQBP1-induced nuclear inclusions is dramatically increased by the co-expression of the pre-mRNA splicing factor SIPP1, a protein ligand of PQBP1. These nuclear inclusions did not co-localise with nuclear structures such as nucleoli, coiled bodies, PML bodies, speckles and stress bodies, and were not associated with (in)active chromatin or with nucleic acids. Site-directed mutagenesis showed that the facilitation in the formation of the nuclear inclusions required multiple independent interaction sites between SIPP1 and PQBP1. Moreover, the nuclear inclusions were highly dynamic and their formation did not require energy. Our data suggest that the SIPP1-PQBP1-induced nuclear inclusions are distinct from the protein aggregates that are associated with polyglutamine diseases and represent dynamic nucleoplasmic heteropolymers of SIPP1 and PQBP1.
Nicolaescu
Emilia
E
Laboratory of Biosignaling and Therapeutics, Department of Molecular Cell Biology, University of Leuven, Campus Gasthuisberg, O&N1/Box901, Herestraat 49, B-3000 Leuven, Belgium.
Beullens
Monique
M
Lesage
Bart
B
Keppens
Stefaan
S
Himpens
Bernard
B
Bollen
Mathieu
M
D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D000072260:RNA Splicing Factors
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C119246:PQBP1 protein, human; D000072260:RNA Splicing Factors; C434066:WBP11 protein, human