ER-phagy requires the assembly of actin at sites of contact between the cortical ER and endocytic pits.
ER-phagy requires the assembly of actin at sites of contact between the cortical ER and endocytic pits.
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DOI：
10.1073/pnas.2117554119
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发表时间：
2022-02-08
影响因子：
11.1
通讯作者：
Novick P
中科院分区：
文献类型：
--
作者：
Liu D;Mari M;Li X;Reggiori F;Ferro-Novick S;Novick P
内质网（ER）的一部分被自噬（ER-吞噬）降解，以响应饥饿或错误折叠蛋白质的积累。我们表明，ER-吞噬需要组装肌动蛋白的ER片和细胞膜上的内吞坑的边缘之间的接触点。肌动蛋白组装可能有助于将携带选择性自噬受体Atg 40的ER元件带入细胞内部，在那里它与Atg 11相关联，Atg 11是一种为自噬体组装募集组分所需的支架。了解ER区域被选择用于降解和隔离在自噬体内的机制可能有助于开发新的方法来治疗由ER内错误折叠蛋白质积累引起的疾病。内质网（ER）的片段通过称为ER吞噬的自噬过程选择性地递送到溶酶体（哺乳动物）或液泡（酵母），以响应饥饿或错误折叠蛋白质的积累。对酿酒酵母缺失文库的筛选将end 3 Δ鉴定为候选敲除菌株，其在饥饿条件下ER-吞噬有缺陷，但不存在大量自噬。我们发现，End 3及其稳定的结合伙伴Pan 1的损失，或Arp 2/3复合物的抑制，这是由End 3-Pan 1复合物耦合到内吞陷窝，阻断皮质ER自噬受体，Atg 40，与自噬体组装支架蛋白Atg 11的关联。ER吞噬还需要连接皮层ER片边缘和内吞凹的膜接触位点模块，其由Scs 2或Scs 22、Osh 2或Osh 3以及Myo 3或Myo 5组成。Atg 40和Scs 2都集中在ER片的边缘，并且可以彼此交联。我们的研究结果是一致的模型，其中肌动蛋白组装在皮质ER和内吞凹之间的接触部位，有助于ER隔离成自噬体。
Portions of the endoplasmic reticulum (ER) are degraded by autophagy (ER-phagy) in response to starvation or the accumulation of misfolded proteins. We show that ER-phagy requires assembly of actin at sites of contact between the edges of ER sheets and endocytic pits on the plasma membrane. Actin assembly may help to bring an element of the ER carrying the selective autophagy receptor Atg40 into the cell interior, where it associates with Atg11, a scaffold needed to recruit components for autophagosome assembly. Understanding the mechanism by which regions of the ER are selected for degradation and sequestered within autophagosomes may help in the development of novel approaches to treat diseases that result from the accumulation of misfolded proteins within the ER. Fragments of the endoplasmic reticulum (ER) are selectively delivered to the lysosome (mammals) or vacuole (yeast) in response to starvation or the accumulation of misfolded proteins through an autophagic process known as ER-phagy. A screen of the Saccharomyces cerevisiae deletion library identified end3Δ as a candidate knockout strain that is defective in ER-phagy during starvation conditions, but not bulk autophagy. We find that loss of End3 and its stable binding partner Pan1, or inhibition of the Arp2/3 complex that is coupled by the End3-Pan1 complex to endocytic pits, blocks the association of the cortical ER autophagy receptor, Atg40, with the autophagosomal assembly scaffold protein Atg11. The membrane contact site module linking the rim of cortical ER sheets and endocytic pits, consisting of Scs2 or Scs22, Osh2 or Osh3, and Myo3 or Myo5, is also needed for ER-phagy. Both Atg40 and Scs2 are concentrated at the edges of ER sheets and can be cross-linked to each other. Our results are consistent with a model in which actin assembly at sites of contact between the cortical ER and endocytic pits contributes to ER sequestration into autophagosomes.
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影响因子：
56.9
作者：
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通讯作者：
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DOI：
10.1073/pnas.2008923117
发表时间：
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影响因子：
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作者：
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通讯作者：
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