Potent and specific Atg8-targeting autophagy inhibitory peptides from giant ankyrins
Potent and specific Atg8-targeting autophagy inhibitory peptides from giant ankyrins
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来自巨型锚蛋白的有效且特异的 Atg8 靶向自噬抑制肽
DOI：
10.1038/s41589-018-0082-8
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发表时间：
2018-08-01
影响因子：
14.8
通讯作者：
Zhang, Mingjie
中科院分区：
文献类型：
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作者：
Li, Jianchao;Zhu, Ruichi;Zhang, Mingjie
哺乳动物Atg 8家族蛋白是自噬的中心驱动因子，包含六个成员，分为LC 3和GABARAP亚家族。由于它们的高度序列相似性和随之而来的功能重叠，很难描述Atg 8蛋白在自噬中的具体功能。在这里，我们发现了一个超强的GABARAP选择性抑制肽窝藏在270/480 kDa的锚蛋白-G和一个超级有效的泛Atg 8抑制肽从440 kDa的锚蛋白-B。结构研究阐明了Atg 8结合效力和选择性的肽的机制，揭示了一般Atg 8结合序列基序，并允许开发一个更GABARAP选择性抑制肽。这些肽在培养的细胞中表达时有效地阻断了自噬。这些锚衍生肽在秀丽隐杆线虫中的表达也抑制自噬，导致p62同源物SQST-1的积累，延迟发育和缩短寿命。因此，这些可遗传编码的自噬抑制肽可用于在活动物中时空地封闭自噬。
The mammalian Atg8 family proteins are central drivers of autophagy and contain six members, classified into the LC3 and GABARAP subfamilies. Due to their high sequence similarity and consequent functional overlaps, it is difficult to delineate specific functions of Atg8 proteins in autophagy. Here we discover a super-strong GABARAP-selective inhibitory peptide harbored in 270/480 kDa ankyrin-G and a super-potent pan-Atg8 inhibitory peptide from 440 kDa ankyrin-B. Structural studies elucidate the mechanism governing the Atg8 binding potency and selectivity of the peptides, reveal a general Atg8-binding sequence motif, and allow development of a more GABARAP-selective inhibitory peptide. These peptides effectively blocked autophagy when expressed in cultured cells. Expression of these ankyrin-derived peptides in Caenorhabditis elegans also inhibited autophagy, causing accumulation of the p62 homolog SQST-1, delayed development and shortened life span. Thus, these genetically encodable autophagy inhibitory peptides can be used to occlude autophagy spatiotemporally in living animals.