LC3/GABARAPs drive ubiquitin-independent recruitment of Optineurin and NDP52 to amplify mitophagy
LC3/GABARAPs drive ubiquitin-independent recruitment of Optineurin and NDP52 to amplify mitophagy
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DOI：
10.1038/s41467-019-08335-6
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发表时间：
2019-01-24
影响因子：
16.6
通讯作者：
Lazarou, Michael
中科院分区：
文献类型：
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作者：
Padman, Benjamin Scott;Thanh Ngoc Nguyen;Lazarou, Michael
目前选择性自噬的模型表明，包括Optineurin和NDP52在内的自噬受体将货物与自噬体膜联系起来。这被认为是通过自噬受体通过LC3相互作用区(LIR)与Atg8同源物(LC3/GABARAPs)结合而发生的。因此，自噬受体内的LIR基序被广泛认为是选择性封存货物所必需的。在这里，我们证明了OPTN和NDP52中的LIR基序对于PINK1/Parkin有丝分裂过程中Atg8的招募和选择性是必不可少的。相反，Atg8通过LIR基序在介导OPTN和NDP52非依赖泛素的募集到不断生长的吞噬体膜中发挥关键作用。OPTN和NDP52的额外招募通过ATG8依赖的正反馈环放大了有丝分裂吞噬作用。我们发现LIR基序在有丝分裂吞噬放大中的作用不是选择性的，而是指向了一种通用的机制，通过该机制，Atg8可以招募自噬因子来驱动自噬小体的生长并放大选择性自噬。
Current models of selective autophagy dictate that autophagy receptors, including Optineurin and NDP52, link cargo to autophagosomal membranes. This is thought to occur via autophagy receptor binding to Atg8 homologs (LC3/GABARAPs) through an LC3 interacting region (LIR). The LIR motif within autophagy receptors is therefore widely recognised as being essential for selective sequestration of cargo. Here we show that the LIR motif within OPTN and NDP52 is dispensable for Atg8 recruitment and selectivity during PINK1/Parkin mitophagy. Instead, Atg8s play a critical role in mediating ubiquitin-independent recruitment of OPTN and NDP52 to growing phagophore membranes via the LIR motif. The additional recruitment of OPTN and NDP52 amplifies mitophagy through an Atg8-dependent positive feedback loop. Rather than functioning in selectivity, our discovery of a role for the LIR motif in mitophagy amplification points toward a general mechanism by which Atg8s can recruit autophagy factors to drive autophagosome growth and amplify selective autophagy.