ESCRT-0 dysfunction compromises autophagic degradation of protein aggregates and facilitates ER stress-mediated neurodegeneration via apoptotic and necroptotic pathways.
ESCRT-0 dysfunction compromises autophagic degradation of protein aggregates and facilitates ER stress-mediated neurodegeneration via apoptotic and necroptotic pathways.
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DOI：
10.1038/srep24997
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发表时间：
2016-04-26
影响因子：
4.6
通讯作者：
Tanaka N
中科院分区：
文献类型：
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作者：
Oshima R;Hasegawa T;Tamai K;Sugeno N;Yoshida S;Kobayashi J;Kikuchi A;Baba T;Futatsugi A;Sato I;Satoh K;Takeda A;Aoki M;Tanaka N
运输所需的内体分选 (ESCRT) 复合物协调泛素化蛋白的内溶酶体分选、多泡体形成和自噬降解。 ESRT 通路的缺陷与许多神经退行性疾病有关，但将其与神经退行性疾病联系起来的潜在分子机制仍然未知。在这项研究中，我们发现前脑特异性消融 ESCRT-0/Hrs 会导致海马神经元细胞明显丢失，并伴有泛素化蛋白的积累，包括 α-突触核蛋白、TDP-43 和亨廷顿蛋白以及自噬底物 SQSTM1/p62。与此相一致的是，培养细胞中 Hrs 的沉默不仅会导致 α-突触核蛋白和 TDP-43 的积累，以及自噬通量受损，还会通过诱导 ER 应激，随后激活 JNK 和 RIPK1（坏死性凋亡的关键调节因子）来抑制细胞活力。此外，necrostatin-1（RIPK1 的特异性抑制剂）和 pan-caspase 抑制剂部分降低了 Hrs 沉默细胞中的神经毒性。总而言之，这些发现表明，神经系统中 ESCRT-0/Hrs 的破坏会损害神经退行性疾病相关蛋白的自噬/溶酶体降解，从而引发内质网应激介导的细胞凋亡和坏死性细胞死亡。
Endosomal sorting required for transport (ESCRT) complexes orchestrate endo-lysosomal sorting of ubiquitinated proteins, multivesicular body formation and autophagic degradation. Defects in the ESCRT pathway have been implicated in many neurodegenerative diseases, but the underlying molecular mechanisms that link them to neurodegeneration remain unknown. In this study, we showed that forebrain-specific ablation of ESCRT-0/Hrs induced marked hippocampal neuronal cell loss accompanied by the accumulation of ubiquitinated proteins, including α-synuclein, TDP-43 and huntingtin as well as the autophagic substrate SQSTM1/p62. Consistent with this, silencing of Hrs in cultured cells not only led to α-synuclein and TDP-43 accumulation in addition to impaired autophagic flux but also suppressed cell viability through the induction of ER stress followed by the activation of JNK and RIPK1, a key regulator of necroptosis. Moreover, necrostatin-1, a specific inhibitor of RIPK1, and pan-caspase inhibitors partially reduced the neurotoxicity in the Hrs-silenced cells. Altogether, these findings suggest that the disruption of ESCRT-0/Hrs in the nervous system compromises autophagic/lysosomal degradation of neurodegenerative disease-related proteins, which thereby triggers ER stress-mediated apoptotic and necroptotic cell death.