Nicolaescu Emilia, Beullens Monique, Lesage Bart, Keppens Stefaan, Himpens Bernard, Bollen Mathieu
Laboratory of Biosignaling and Therapeutics, Department of Molecular Cell Biology, University of Leuven, Campus Gasthuisberg, O&N1/Box901, Herestraat 49, B-3000 Leuven, Belgium.
Eur J Cell Biol. 2008 Oct;87(10):817-29. doi: 10.1016/j.ejcb.2008.05.001. Epub 2008 Jul 2.
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.
PQBP1即多聚谷氨酰胺序列结合蛋白1，与进行性神经退行性疾病有关，如脊髓小脑共济失调，这类疾病是由关键调节蛋白中多聚谷氨酰胺重复序列的扩增引起的。PQBP1的过表达会导致核内包涵体的形成，这让人联想到在多聚谷氨酰胺疾病中检测到的蛋白质聚集体。我们在此表明，前体mRNA剪接因子SIPP1（PQBP1的一种蛋白质配体）的共表达会显著增加PQBP1诱导的核内包涵体的出现。这些核内包涵体不与核仁、卷曲小体、PML小体、斑点和应激小体等核结构共定位，也不与（非）活性染色质或核酸相关。定点诱变表明，核内包涵体形成的促进需要SIPP1和PQBP1之间多个独立的相互作用位点。此外，核内包涵体具有高度动态性，其形成不需要能量。我们的数据表明，SIPP1-PQBP1诱导的核内包涵体与多聚谷氨酰胺疾病相关的蛋白质聚集体不同，代表了SIPP1和PQBP1的动态核质异聚物。
