Rapid induction of p62 and GABARAPL1 upon proteasome inhibition promotes survival before autophagy activation.
Rapid induction of p62 and GABARAPL1 upon proteasome inhibition promotes survival before autophagy activation.
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DOI：
10.1083/jcb.201708168
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发表时间：
2018-05-07
期刊：
影响因子：
--
通讯作者：
Goldberg A
中科院分区：
文献类型：
--
作者：
Sha Z;Schnell HM;Ruoff K;Goldberg A
细胞被认为通过使用其他降解途径(如自噬)来适应蛋白酶体的抑制。Shae等人的研究。现在报道，细胞在蛋白酶体被抑制后迅速诱导GABARAPL1和p62，但这通过在细胞诱导其他ATG基因和激活自噬之前很久就隔离泛素化和SUM化的蛋白来促进细胞存活。蛋白酶体抑制剂被用作研究工具和治疗多发性骨髓瘤，在一些神经退行性疾病中蛋白酶体活性降低。因此，我们研究了细胞如何补偿蛋白酶体的抑制。在4h内，蛋白酶体抑制剂诱导GABARAPL1(而不是其他自噬基因)和p62的显著和选择性诱导，p62与泛素化蛋白和GABARAPL1结合在自噬小体上。P62或GABARAPL1基因的敲除降低了蛋白酶体抑制后的细胞存活率。P62的诱导需要转录因子核因子(红系衍生的2)样蛋白1(Nrf1)，它同时诱导蛋白酶体基因。在蛋白酶体抑制剂作用20小时后，细胞通过不依赖于Nrf1的机制激活自噬和大多数自噬基因的表达。虽然p62促进泛素化蛋白与自噬小体的结合，但它在神经母细胞瘤细胞中的敲除阻止了核周侵袭体中泛素结合物的积聚和核包涵体中Sumoylated蛋白的积聚，但并未减少泛素化蛋白的降解。因此，一旦蛋白酶体被抑制，细胞就会迅速诱导p62的表达，这主要是通过隔离包涵体中泛素化的蛋白来提高存活率。
Cells are thought to adapt to proteasome inhibition by using alternative pathways for degradation such as autophagy. Sha et al. now report that cells rapidly induce GABARAPL1 and p62 upon proteasome inhibition, but this promotes cell survival by sequestering ubiquitinated and sumoylated proteins long before the cells induce other Atg genes and activate autophagy. Proteasome inhibitors are used as research tools and to treat multiple myeloma, and proteasome activity is diminished in several neurodegenerative diseases. We therefore studied how cells compensate for proteasome inhibition. In 4 h, proteasome inhibitor treatment caused dramatic and selective induction of GABARAPL1 (but not other autophagy genes) and p62, which binds ubiquitinated proteins and GABARAPL1 on autophagosomes. Knockdown of p62 or GABARAPL1 reduced cell survival upon proteasome inhibition. p62 induction requires the transcription factor nuclear factor (erythroid-derived 2)-like 1 (Nrf1), which simultaneously induces proteasome genes. After 20-h exposure to proteasome inhibitors, cells activated autophagy and expression of most autophagy genes by an Nrf1-independent mechanism. Although p62 facilitates the association of ubiquitinated proteins with autophagosomes, its knockdown in neuroblastoma cells blocked the buildup of ubiquitin conjugates in perinuclear aggresomes and of sumoylated proteins in nuclear inclusions but did not reduce the degradation of ubiquitinated proteins. Thus, upon proteasome inhibition, cells rapidly induce p62 expression, which enhances survival primarily by sequestering ubiquitinated proteins in inclusions.
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影响因子：
64.5
作者：
Kawaguchi, Y;Kovacs, JJ;Yao, TP
通讯作者：
Yao, TP
影响因子：
11.2
作者：
Fels DR;Ye J;Segan AT;Kridel SJ;Spiotto M;Olson M;Koong AC;Koumenis C
通讯作者：
Koumenis C
影响因子：
5.7
作者：
Ding WX;Ni HM;Gao W;Chen X;Kang JH;Stolz DB;Liu J;Yin XM
通讯作者：
Yin XM
影响因子：
16
作者：
Duran A;Amanchy R;Linares JF;Joshi J;Abu-Baker S;Porollo A;Hansen M;Moscat J;Diaz-Meco MT
通讯作者：
Diaz-Meco MT
影响因子：
13.3
作者：
Demishtein, Alik;Fraiberg, Milana;Navon, Ami
通讯作者：
Navon, Ami