Sheehan Brendan K, Orefice Nicola S, Peng Yajing, Shapiro Samantha L, Puglielli Luigi
Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
iScience. 2021 Mar 16;24(4):102315. doi: 10.1016/j.isci.2021.102315. eCollection 2021 Apr 23.
The acetylation of ATG9A within the endoplasmic reticulum (ER) lumen regulates the induction of reticulophagy. ER acetylation is ensured by AT-1/SLC33A1, a membrane transporter that maintains the cytosol-to-ER flux of acetyl-CoA. Defective AT-1 activity, as caused by heterozygous/homozygous mutations and gene duplication events, results in severe disease phenotypes. Here, we show that although the acetylation of ATG9A occurs in the ER lumen, the induction of reticulophagy requires ATG9A to engage FAM134B and SEC62 on the cytosolic side of the ER. To address this conundrum, we resolved the ATG9A interactome in two mouse models of AT-1 dysregulation: AT-1 sTg, a model of systemic AT-1 overexpression with hyperacetylation of ATG9A, and AT-1, a model of AT-1 haploinsufficiency with hypoacetylation of ATG9A. We identified CALR and HSPB1 as two ATG9A partners that regulate the induction of reticulophagy as a function of ATG9A acetylation and discovered that ATG9A associates with several proteins that maintain ER proteostasis.
内质网（ER）腔内ATG9A的乙酰化作用调控网织红细胞自噬的诱导。AT-1/SLC33A1可确保ER的乙酰化，它是一种维持乙酰辅酶A从胞质溶胶到内质网通量的膜转运蛋白。由杂合/纯合突变和基因复制事件导致的AT-1活性缺陷会引发严重的疾病表型。在此，我们表明，尽管ATG9A的乙酰化发生在内质网腔内，但网织红细胞自噬的诱导需要ATG9A在内质网胞质侧与FAM134B和SEC62结合。为解决这一难题，我们在两种AT-1失调的小鼠模型中解析了ATG9A相互作用组：AT-1 sTg，一种ATG9A发生超乙酰化的全身性AT-1过表达模型；以及AT-1，一种ATG9A发生低乙酰化的AT-1单倍体不足模型。我们鉴定出CALR和HSPB1是两个作为ATG9A乙酰化功能调控网织红细胞自噬诱导的ATG9A伴侣，并发现ATG9A与几种维持内质网蛋白质稳态的蛋白质相关联。
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