Institute for Cell Biology, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany.
PLoS One. 2011 Jan 20;6(1):e16398. doi: 10.1371/journal.pone.0016398.
The maturation of mouse macrophages and dendritic cells involves the transient deposition of ubiquitylated proteins in the form of dendritic cell aggresome-like induced structures (DALIS). Transient DALIS formation was used here as a paradigm to study how mammalian cells influence the formation and disassembly of protein aggregates through alterations of their proteostasis machinery. Co-chaperones that modulate the interplay of Hsc70 and Hsp70 with the ubiquitin-proteasome system (UPS) and the autophagosome-lysosome pathway emerged as key regulators of this process. The chaperone-associated ubiquitin ligase CHIP and the ubiquitin-domain protein BAG-1 are essential for DALIS formation in mouse macrophages and bone-marrow derived dendritic cells (BMDCs). CHIP also cooperates with BAG-3 and the autophagic ubiquitin adaptor p62 in the clearance of DALIS through chaperone-assisted selective autophagy (CASA). On the other hand, the co-chaperone HspBP1 inhibits the activity of CHIP and thereby attenuates antigen sequestration. Through a modulation of DALIS formation CHIP, BAG-1 and HspBP1 alter MHC class I mediated antigen presentation in mouse BMDCs. Our data show that the Hsc/Hsp70 co-chaperone network controls transient protein aggregation during maturation of professional antigen presenting cells and in this way regulates the immune response. Similar mechanisms may modulate the formation of aggresomes and aggresome-like induced structures (ALIS) in other mammalian cell types.
小鼠巨噬细胞和树突状细胞的成熟涉及泛素化蛋白以树突状细胞聚集物样诱导结构 (DALIS) 的形式的短暂沉积。在这里，瞬态 DALIS 形成被用作研究哺乳动物细胞如何通过改变其蛋白质稳态机制来影响蛋白质聚集体的形成和解体的范例。调节 Hsc70 和 Hsp70 与泛素-蛋白酶体系统 (UPS) 和自噬体-溶酶体途径相互作用的共伴侣作为该过程的关键调节剂出现。伴侣相关泛素连接酶 CHIP 和泛素结构域蛋白 BAG-1 对于小鼠巨噬细胞和骨髓来源的树突状细胞 (BMDC) 中的 DALIS 形成是必不可少的。CHIP 还与 BAG-3 和自噬泛素衔接蛋白 p62 合作，通过伴侣辅助的选择性自噬 (CASA) 清除 DALIS。另一方面，共伴侣 HspBP1 抑制 CHIP 的活性，从而减弱抗原隔离。通过调节 DALIS 形成，CHIP、BAG-1 和 HspBP1 改变了小鼠 BMDC 中 MHC I 介导的抗原呈递。我们的数据表明，Hsc/Hsp70 共伴侣网络控制着专业抗原呈递细胞成熟过程中短暂的蛋白质聚集，从而调节免疫反应。类似的机制可能调节其他哺乳动物细胞类型中聚集体和聚集物样诱导结构 (ALIS) 的形成。
