Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein.
Expression of misfolded protein in cultured cells frequently leads to the formation of juxtanuclear inclusions that have been termed 'aggresomes'. Aggresome formation is an active cellular response that involves trafficking of the offending protein along microtubules, reorganization of intermediate filaments and recruitment of components of the ubiquitin proteasome system. Whether aggresomes are benevolent or noxious is unknown, but they are of particular interest because of the appearance of similar inclusions in protein deposition diseases. Here we present evidence that aggresomes serve a cytoprotective function and are associated with accelerated turnover of mutant proteins. We show that mutant androgen receptor (AR), the protein responsible for X-linked spinobulbar muscular atrophy, forms insoluble aggregates and is toxic to cultured cells. Mutant AR was also found to form aggresomes in a process distinct from aggregation. Molecular and pharmacological interventions were used to disrupt aggresome formation, revealing their cytoprotective function. Aggresome-forming proteins were found to have an accelerated rate of turnover, and this turnover was slowed by inhibition of aggresome formation. Finally, we show that aggresome-forming proteins become membrane-bound and associate with lysosomal structures. Together, these findings suggest that aggresomes are cytoprotective, serving as cytoplasmic recruitment centers to facilitate degradation of toxic proteins.
Taylor
J Paul
JP
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Building 10, Room 3B-14, Bethesda, MD 20892-1250, USA. taylorjp@ninds.nih.gov
Tanaka
Fumiaki
F
Robitschek
Jon
J
Sandoval
C Miguel
CM
Taye
Addis
A
Markovic-Plese
Silva
S
Fischbeck
Kenneth H
KH
D001343:Autophagy; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation; D010455:Peptides; D046988:Proteasome Endopeptidase Complex; D017510:Protein Folding; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics; D014162:Transfection
D009097:Multienzyme Complexes; D010455:Peptides; D011506:Proteins; D011944:Receptors, Androgen; C097188:polyglutamine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex