Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone.
Spinal bulbar muscular atrophy is a neurodegenerative disorder caused by a polyglutamine expansion in the androgen receptor (AR). We show in transiently transfected HeLa cells that an AR containing 48 glutamines (ARQ48) accumulates in a hormone-dependent manner in both cytoplasmic and nuclear aggregates. Electron microscopy reveals both types of aggregates to have a similar ultrastructure. ARQ48 aggregates sequester mitochondria and steroid receptor coactivator 1 and stain positively for NEDD8, Hsp70, Hsp90 and HDJ-2/HSDJ. Co-expression of HDJ-2/HSDJ significantly represses aggregate formation. ARQ48 aggregates also label with antibodies recognizing the PA700 proteasome caps but not 20S core particles. These results suggest that ARQ48 accumulates due to protein misfolding and a breakdown in proteolytic processing. Furthermore, the homeostatic disturbances associated with aggregate formation may affect normal cell function.
Stenoien
D L
DL
Department of Cell Biology, Baylor College of Medicine and VA Medical Center, One Baylor Plaza, Houston, TX 77030, USA.
Cummings
C J
CJ
Adams
H P
HP
Mancini
M G
MG
Patel
K
K
DeMartino
G N
GN
Marcelli
M
M
Weigel
N L
NL
Mancini
M A
MA
D000255:Adenosine Triphosphate / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism / Q000648:ultrastructure; D049452:Green Fluorescent Proteins; D050956:HSP40 Heat-Shock Proteins; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D051548:Histone Acetyltransferases; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008938:Mitosis; D009097:Multienzyme Complexes / Q000378:metabolism*; D000075687:NEDD8 Protein; D056920:Nuclear Receptor Coactivator 1; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; C107481:DNAJA1 protein, human; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008164:Luminescent Proteins; D009097:Multienzyme Complexes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D010455:Peptides; D011944:Receptors, Androgen; D011987:Receptors, Steroid; D011994:Recombinant Proteins; D014157:Transcription Factors; D014452:Ubiquitins; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D000255:Adenosine Triphosphate; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex