FAM134B的乙酰化修饰在内质网自噬中的功能研究

Autophagy cargoes including organelles, pathogens and protein aggregates can be specifically recognized and degraded by certain type of selective autophagy, which plays essential roles in maintaining cellular homeostasis. The specificity in substrate recognition in selective autophagy is governed by a serial of receptors, which act as bridging molecules by simultaneously binding to autophagic cargoes and to the lipidated ATG8 family members on autophagic membranes. The biological functions of selective autophagy receptors can be regulated by post-translational protein modifications. However, it is not known whether acetylation directly controls autophagy receptors. Here, we report that an ER-phagy receptor FAM134B is acetylated by CBP acetyltransferase, which is required for maximal FAM134B oligomerization, ER scission and ER-phagy both in vitro and in vivo. Conversely, Sirtuin 7 deacetylated FAM134B to temper its activities in ER-phagy to avoid excessive or unnecessary ER degradation. Together, this work not only demonstrates that the dynamics of acetylation and deacetylation directly regulates selective autophagy by modulating receptor function, but also provides further mechanistic insights into how ER-phagy protein machinery perceives upstream signals for fine-tuning of ER homeostasis.

细胞器，病原体和蛋白质聚集体等自噬底物可以通过某种类型的选择性自噬来特异性识别和降解，这类自噬在维持细胞稳态中起着至关重要的作用。选择性自噬中底物识别的特异性受一系列受体的调控，这些受体通过同时与自噬底物和自噬膜上脂化的ATG8家族成员结合而起到桥接分子的作用。选择性自噬受体的生物学功能可以通过蛋白翻译后修饰来调节。但是，尚不知道乙酰化是否直接参与选择性自噬受体的调控。本研究将揭示ER-phagy受体蛋白FAM134B能被乙酰转移酶CBP乙酰化，这是FAM134B多聚体化，ER片段化和ER-phagy所必需的；相反，去乙酰化酶Sirt7则使FAM134B脱乙酰基以调节其在ER-phagy中的活性，从而避免过度或不必要的ER降解。总之，这项工作将不仅表明乙酰化和去乙酰化的动力学通过调节受体功能直接调控选择性自噬，而且还为ER-phagy蛋白机器如何感知上游信号以调节ER稳态提供机制性见解。

巨自噬（自噬）是利用一系列受体来特异性识别和降解受损细胞器等自噬底物以维持细胞内稳态。上游信号通过磷酸化等蛋白质翻译后修饰（PTM）时空调控选择性自噬受体的生物学功能。然而，目前尚不清楚乙酰化如何直接调控选择性自噬受体。在这里，我们报道了一种内质网自噬受体FAM134B被乙酰转移酶CBP乙酰化后诱发过度的内质网自噬。此外，FAM134B乙酰化促进CAMKII介导的磷酸化以维持更温和的内质网自噬模式。相反，去乙酰化酶SIRT7去乙酰化FAM134B以缓和其在内质网自噬中的活性来避免内质网过度降解。总之，这项工作为内质网自噬受体如何感知环境信号以微调内质网稳态提供了进一步的机制见解，并证明了核衍生因子如何通过调节内质网自噬来控制内质网应激。