Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection.
Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection.
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DOI：
10.1083/jcb.201005012
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发表时间：
2010-11-01
期刊：
影响因子：
--
通讯作者：
Kopito RR
中科院分区：
文献类型：
--
作者：
Riley BE;Kaiser SE;Shaler TA;Ng AC;Hara T;Hipp MS;Lage K;Xavier RJ;Ryu KY;Taguchi K;Yamamoto M;Tanaka K;Mizushima N;Komatsu M;Kopito RR
失活的必要的自噬基因Atg 5的结果在选择性聚集倾向的蛋白质的底物泛素化独立的积累。小鼠自噬的基因切除导致肝脏和大脑变性，伴随着泛素（Ub）包涵体的出现，这被认为支持泛素化作为选择性自噬的顺式作用信号的假设。我们发现，组织特异性破坏的基本自噬基因Atg 5和Atg 7导致所有可检测的Ub-Ub拓扑结构的积累，反对任何特定的Ub连接作为一个特定的自噬信号的假设。Atg 7 −/−肝脏和大脑中Ub结合物的增加被同时敲除p62或Nrf 2完全抑制。我们开发了一种新的细胞培养物中选择性自噬的测定方法，该方法表明Atg 5的失活导致聚集倾向蛋白的选择性积累，并且这与底物泛素化的增加无关。我们提出，蛋白质寡聚化驱动自噬底物的选择和自噬缺陷的情况下聚Ub链的积累是Nrf 2依赖性应激反应途径激活的间接后果。
Inactivation of the essential autophagy gene Atg5 results in selective accumulation of aggregation-prone proteins independently of substrate ubiquitination. Genetic ablation of autophagy in mice leads to liver and brain degeneration accompanied by the appearance of ubiquitin (Ub) inclusions, which has been considered to support the hypothesis that ubiquitination serves as a cis-acting signal for selective autophagy. We show that tissue-specific disruption of the essential autophagy genes Atg5 and Atg7 leads to the accumulation of all detectable Ub–Ub topologies, arguing against the hypothesis that any particular Ub linkage serves as a specific autophagy signal. The increase in Ub conjugates in Atg7−/− liver and brain is completely suppressed by simultaneous knockout of either p62 or Nrf2. We exploit a novel assay for selective autophagy in cell culture, which shows that inactivation of Atg5 leads to the selective accumulation of aggregation-prone proteins, and this does not correlate with an increase in substrate ubiquitination. We propose that protein oligomerization drives autophagic substrate selection and that the accumulation of poly-Ub chains in autophagy-deficient circumstances is an indirect consequence of activation of Nrf2-dependent stress response pathways.
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影响因子：
4.1
作者：
DOHERTY, FJ;OSBORN, NU;MAYER, RJ
通讯作者：
MAYER, RJ
影响因子：
14.9
作者：
Benita Y;Kikuchi H;Smith AD;Zhang MQ;Chung DC;Xavier RJ
通讯作者：
Xavier RJ
影响因子：
14.9
作者：
Bairoch, Amos;Bougueleret, Lydie;Zhang, Jian
通讯作者：
Zhang, Jian
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y