Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy.
Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy.
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DOI：
10.1038/nature13148
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发表时间：
2014-05-01
期刊：
影响因子：
64.8
通讯作者：
Kimmelman, Alec C.
中科院分区：
文献类型：
--
作者：
Mancias, Joseph D.;Wang, Xiaoxu;Gygi, Steven P.;Harper, J. Wade;Kimmelman, Alec C.
自噬是蛋白质和细胞器被隔离在称为自噬体的双膜结构中并被递送到溶酶体进行降解的过程，在癌症和神经变性等疾病中至关重要。我们对这一过程的大部分理解都来自对大量细胞质自噬的分析，但我们对特定货物（包括细胞器、蛋白质或细胞内病原体）如何被靶向选择性自噬的理解是有限的。我们采用定量蛋白质组学来鉴定一组新的和已知的自噬体富集蛋白，包括货物受体。与已知的货物受体一样，NCOA 4在自噬体中高度富集，并与将货物-受体复合物募集到自噬体中的ATG 8蛋白相关。NCOA 4相关蛋白的无偏鉴定揭示了铁蛋白重链和轻链，铁填充笼结构的组分，其保护细胞免受活性铁物质的影响，但通过自噬降解以通过未知机制释放铁。我们发现铁蛋白向溶酶体的传递需要NCOA 4，并且NCOA 4缺陷细胞不能降解铁蛋白导致生物可利用的细胞内铁减少。这项工作确定了NCOA 4作为铁蛋白（ferritinophagy）自噬周转的选择性货物受体，对铁稳态至关重要，并为进一步解剖自噬体货物受体连接提供了资源。
Autophagy, the process by which proteins and organelles are sequestered in double-membrane structures called autophagosomes and delivered to lysosomes for degradation, is critical in diseases such as cancer and neurodegeneration. Much of our understanding of this process has emerged from analysis of bulk cytoplasmic autophagy, but our understanding of how specific cargo including organelles, proteins, or intracellular pathogens are targeted for selective autophagy is limited. We employed quantitative proteomics to identify a cohort of novel and known autophagosome-enriched proteins, including cargo receptors. Like known cargo receptors, NCOA4 was highly enriched in autophagosomes, and associated with ATG8 proteins that recruit cargo-receptor complexes into autophagosomes. Unbiased identification of NCOA4-associated proteins revealed ferritin heavy and light chains, components of an iron-filled cage structure that protects cells from reactive iron species but is degraded via autophagy to release iron through an unknown mechanism. We found that delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin leads to decreased bioavailable intracellular iron. This work identifies NCOA4 as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy) critical for iron homeostasis and provides a resource for further dissection of autophagosomal cargo-receptor connectivity.
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影响因子：
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作者：
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