Autophagy-mediated clearance of aggresomes is not a universal phenomenon.
Aggresomes are juxtanuclear inclusion bodies that have been proposed to act as staging grounds for the disposal of protein aggregates via the autophagic route. To examine whether the composition of an aggresome influences its clearance by autophagy, we ectopically expressed a variety of aggregation-prone proteins in cultured cells to generate aggresomes that differ in their protein content. We found that whereas aggresomes generated in cells expressing mutant huntingtin or mutant tau, or co-expressing synphilin-1 and alpha-synuclein, are amenable to clearance by autophagy, those produced in AIMP2 (p38)- or mutant desmin-expressing cells are apparently resistant to autophagic clearance. Notably, AIMP2 (p38)- and desmin-positive inclusions fail to recruit key components of the autophagic/lysosomal system. However, by altering the composition of inclusions, 'autophagy-resistant' aggresomes could be rendered 'autophagy-susceptible'. Taken together, our results demonstrate that not all aggresomes are efficiently primed for autophagic clearance and highlight a certain degree of selectivity for the supposedly non-discriminative pathway.
Wong
Esther S P
ES
Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore.
Tan
Jeanne M M
JM
Soong
Wen-E
WE
Hussein
Kamila
K
Nukina
Nobuyuki
N
Dawson
Valina L
VL
Dawson
Ted M
TM
Cuervo
Ana Maria
AM
Lim
Kah-Leong
KL
D000818:Animals; D001343:Autophagy; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D000071058:Huntingtin Protein; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000503:physiopathology*; D009687:Nuclear Proteins
D002352:Carrier Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C118958:SNCAIP protein, human