Institute of Pathobiochemistry, University Medical Center, Johannes Gutenberg University, Duesbergweg 6, Mainz 55099, Germany.
EMBO Rep. 2011 Feb;12(2):149-56. doi: 10.1038/embor.2010.203. Epub 2011 Jan 21.
Increasing evidence indicates the existence of selective autophagy pathways, but the manner in which substrates are recognized and targeted to the autophagy system is poorly understood. One strategy is transport of a particular substrate to the aggresome, a perinuclear compartment with high autophagic activity. In this paper, we identify a new cellular pathway that uses the specificity of heat-shock protein 70 (Hsp70) to misfolded proteins as the basis for aggresome-targeting and autophagic degradation. This pathway is regulated by the stress-induced co-chaperone Bcl-2-associated athanogene 3 (BAG3), which interacts with the microtubule-motor dynein and selectively directs Hsp70 substrates to the motor and thereby to the aggresome. Notably, aggresome-targeting by BAG3 is distinct from previously described mechanisms, as it does not depend on substrate ubiquitination.
越来越多的证据表明存在选择性自噬途径，但对于底物如何被识别并靶向自噬系统的机制仍了解甚少。一种策略是将特定的底物运输到聚集体（aggresome），聚集体是一种具有高自噬活性的核周隔室。在本文中，我们发现了一种新的细胞途径，该途径利用热休克蛋白 70（Hsp70）对错误折叠蛋白的特异性作为聚集体靶向和自噬降解的基础。该途径受应激诱导的伴侣蛋白 Bcl-2 相关抗凋亡基因 3（BAG3）的调节，BAG3 与微管动力蛋白 dynein 相互作用，选择性地将 Hsp70 底物引导至该动力蛋白，进而引导至聚集体。值得注意的是，BAG3 的聚集体靶向与先前描述的机制不同，因为它不依赖于底物泛素化。
