SQSTM1/p62-mediated autophagy compensates for loss of proteasome polyubiquitin recruiting capacity
SQSTM1/p62-mediated autophagy compensates for loss of proteasome polyubiquitin recruiting capacity
复制标题
DOI：
10.1080/15548627.2017.1356549
复制
发表时间：
2017-01-01
期刊：
影响因子：
13.3
通讯作者：
Navon, Ami
中科院分区：
文献类型：
--
作者：
Demishtein, Alik;Fraiberg, Milana;Navon, Ami
真核细胞中的蛋白质稳态由2个高度保守的降解途径调节，即泛素-蛋白酶体系统（UPS）和巨噬/自噬。最近的研究表明，这些系统之间的协调和互补串扰在蛋白质静态应激下变得至关重要。然而，在生理条件下，这两种途径之间的分子串扰尚不清楚。在这里，我们描述了一个蛋白酶体底物积累的细胞模型，这是由于PSMD4/S5a和ADRM1这两种蛋白酶体泛素受体的联合下调。该模型揭示了一种代偿性自噬途径，由SQSTM1/p62依赖性清除积累的多泛素化蛋白介导。除了介导将泛素化的物质隔离到吞噬细胞（自噬体的前体）中，SQSTM1在蛋白酶体抑制下对多泛素化聚集体的形成也很重要。最后，我们证明了ATF4（一种快速降解的转录因子）的稳态水平的稳定介导了SQSTM1的上调。这些发现为研究选择性自噬在蛋白酶体溢出反应中调控的分子机制提供了新的见解。
Protein homeostasis in eukaryotic cells is regulated by 2 highly conserved degradative pathways, the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Recent studies revealed a coordinated and complementary crosstalk between these systems that becomes critical under proteostatic stress. Under physiological conditions, however, the molecular crosstalk between these 2 pathways is still far from clear. Here we describe a cellular model of proteasomal substrate accumulation due to the combined knockdown of PSMD4/S5a and ADRM1, the 2 proteasomal ubiquitin receptors. This model reveals a compensatory autophagic pathway, mediated by a SQSTM1/p62-dependent clearance of accumulated polyubiquitinated proteins. In addition to mediating the sequestration of ubiquitinated cargos into phagophores, the precursors to autophagosomes, SQSTM1 is also important for polyubiquitinated aggregate formation upon proteasomal inhibition. Finally, we demonstrate that the concomitant stabilization of steady-state levels of ATF4, a rapidly degraded transcription factor, mediates SQSTM1 upregulation. These findings provide new insight into the molecular mechanisms by which selective autophagy is regulated in response to proteasomal overflow.