Wong Esther S P, Tan Jeanne M M, Soong Wen-E, Hussein Kamila, Nukina Nobuyuki, Dawson Valina L, Dawson Ted M, Cuervo Ana Maria, Lim Kah-Leong
Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore.
Hum Mol Genet. 2008 Aug 15;17(16):2570-82. doi: 10.1093/hmg/ddn157. Epub 2008 May 23.
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.
应激性聚集体是近核包涵体，有人提出其作为通过自噬途径处理蛋白质聚集体的场所。为了研究应激性聚集体的组成是否影响其通过自噬的清除，我们在培养细胞中异位表达了多种易于聚集的蛋白质，以产生蛋白质含量不同的应激性聚集体。我们发现，在表达突变型亨廷顿蛋白或突变型tau蛋白的细胞中产生的应激性聚集体，或共表达突触核蛋白-1和α-突触核蛋白的细胞中产生的应激性聚集体，易于通过自噬清除，而在表达AIMP2（p38）或突变型结蛋白的细胞中产生的应激性聚集体显然对自噬清除具有抗性。值得注意的是，AIMP2（p38）和结蛋白阳性包涵体未能募集自噬/溶酶体系统的关键成分。然而，通过改变包涵体的组成，“自噬抗性”应激性聚集体可变为“自噬敏感”。综上所述，我们的结果表明并非所有应激性聚集体都能有效地启动自噬清除，并突出了这条本应无差别的途径存在一定程度的选择性。
