title: Overexpression of the transcriptional repressor complex BCL-6/BCoR leads to nuclear aggregates distinct from classical aggresomes.
abstract: Nuclear inclusions of aggregated proteins have primarily been characterized for molecules with aberrant poly-glutamine repeats and for mutated or structurally altered proteins. They were termed "nuclear aggresomes" and misfolding was shown to promote association with molecular chaperones and proteasomes. Here, we report that two components of a transcriptional repressor complex (BCL-6 and BCoR) of wildtype amino acid sequence can independently or jointly induce the formation of nuclear aggregates when overexpressed. The observation that the majority of cells rapidly downregulate BCL-6/BCoR levels, supports the notion that expression of these proteins is under tight control. The inclusions occur when BCL-6/BCoR expression exceeds 150-fold of endogenous levels. They preferentially develop in the nucleus by a gradual increase in aggregate size to form large, spheroid structures which are not associated with heat shock proteins or marked by ubiquitin. In contrast, we find the close association of BCL-6/BCoR inclusions with PML bodies and a reduction in aggregation upon the concomitant overexpression of histone deacetylases or heat shock protein 70. In summary, our data offer a perspective on nuclear aggregates distinct from classical "nuclear aggresomes": Large complexes of spheroid structure can evolve in the nucleus without being marked by the cellular machinery for protein refolding and degradation. However, nuclear proteostasis can be restored by balancing the levels of chaperones.
authors.affiliation: Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Buchberger
authors.forename: Miriam
authors.initials: M
authors.lastname: El Harchi
authors.forename: Dietmar
authors.initials: D
authors.lastname: Payrhuber
authors.forename: Anna
authors.initials: A
authors.lastname: Zommer
authors.forename: Dominic
authors.initials: D
authors.lastname: Schauer
authors.forename: Ingrid
authors.initials: I
authors.lastname: Simonitsch-Klupp
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Christine
authors.initials: C
authors.lastname: Brostjan
mesh_terms: D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D008938:Mitosis; D009685:Nuclear Envelope / Q000378:metabolism; D022022:Nuclear Pore / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
chemical_list: C411984:BCOR protein, human; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D012097:Repressor Proteins; D025801:Ubiquitin; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases