Shanghai Center for Plant Stress Biology, Chinese Academy of Sciences, 201602, Shanghai, China.
University of Chinese Academy of Sciences, 100004, Beijing, China.
Nat Commun. 2019 Aug 2;10(1):3492. doi: 10.1038/s41467-019-11480-7.
Endoplasmic reticulum-associated degradation (ERAD) is a unique mechanism to degrade misfolded proteins via complexes containing several highly-conserved ER-anchored ubiquitin ligases such as HMG-CoA reductase degradation1 (Hrd1). Arabidopsis has a similar Hrd1-containing ERAD machinery; however, our knowledge of this complex is limited. Here we report two closely-related Arabidopsis proteins, Protein Associated With Hrd1-1 (PAWH1) and PAWH2, which share a conserved domain with yeast Altered Inheritance of Mitochondria24. PAWH1 and PAWH2 localize to the ER membrane and associate with Hrd1 via EMS-mutagenized Bri1 Suppressor7 (EBS7), a plant-specific component of the Hrd1 complex. Simultaneously elimination of two PAWHs constitutively activates the unfolded protein response and compromises stress tolerance. Importantly, the pawh1 pawh2 double mutation reduces the protein abundance of EBS7 and Hrd1 and inhibits degradation of several ERAD substrates. Our study not only discovers additional plant-specific components of the Arabidopsis Hrd1 complex but also reveals a distinct mechanism for regulating the Hrd1 stability.
内质网相关降解（ERAD）是一种通过含有几种高度保守的内质网锚定泛素连接酶的复合物来降解错误折叠蛋白质的独特机制，例如羟甲基戊二酰辅酶 A 还原酶降解 1（Hrd1）。拟南芥具有类似的含有 Hrd1 的 ERAD 机制；然而，我们对该复合物的了解有限。在这里，我们报告了两种密切相关的拟南芥蛋白，即与 Hrd1-1 相关的蛋白（PAWH1）和 PASH2，它们与酵母改变线粒体遗传 24 具有保守结构域。PAWH1 和 PASH2 定位于内质网膜，并通过 EMS 诱变的 Bri1 抑制剂 7（EBS7）与 Hrd1 相互作用，EBS7 是 Hrd1 复合物的植物特异性成分。同时消除两个 PAWH 会持续激活未折叠蛋白反应并损害应激耐受性。重要的是，pawh1 pawh2 双突变会降低 EBS7 和 Hrd1 的蛋白丰度，并抑制几种 ERAD 底物的降解。我们的研究不仅发现了拟南芥 Hrd1 复合物的其他植物特异性成分，还揭示了调节 Hrd1 稳定性的独特机制。
