Department of Medicine, University of Wisconsin, Madison, WI 53705, USA.
J Biol Chem. 2012 Aug 24;287(35):29921-30. doi: 10.1074/jbc.M112.363911. Epub 2012 Jul 11.
One of the main functions of the unfolded protein response is to ensure disposal of large protein aggregates that accumulate in the lumen of the endoplasmic reticulum (ER) whereas avoiding, at least under nonlethal levels of ER stress, cell death. When tightly controlled, autophagy-dependent ER-associated degradation (ERAD(II)) allows the cell to recover from the transient accumulation of protein aggregates; however, when unchecked, it can be detrimental and cause autophagic cell death/type 2 cell death. Here we show that IRE1/XBP1 controls the induction of autophagy/ERAD(II) during the unfolded protein response by activating the ER membrane transporter SLC33A1/AT-1, which ensures continuous supply of acetyl-CoA into the lumen of the ER. Failure to induce AT-1 leads to widespread autophagic cell death. Mechanistically, the regulation of the autophagic process involves N(ε)-lysine acetylation of Atg9A.
未折叠蛋白反应的主要功能之一是确保内质网（ER）腔中积累的大量蛋白质聚集体的处理，同时避免细胞死亡，至少在 ER 应激的非致死水平下避免。当受到严格控制时，自噬依赖性 ER 相关降解（ERAD(II)）使细胞能够从蛋白质聚集体的短暂积累中恢复；然而，当不受控制时，它可能是有害的，并导致自噬细胞死亡/类型 2 细胞死亡。在这里，我们表明 IRE1/XBP1 通过激活 ER 膜转运蛋白 SLC33A1/AT-1 来控制未折叠蛋白反应期间的自噬/ERAD(II)的诱导，该蛋白确保持续将乙酰辅酶 A 供应到 ER 的腔中。未能诱导 AT-1 会导致广泛的自噬细胞死亡。从机制上讲，自噬过程的调节涉及 Atg9A 的 N(ε)-赖氨酸乙酰化。
