SLC33A1/AT-1 Protein Regulates the Induction of Autophagy Downstream of IRE1/XBP1 Pathway
SLC33A1/AT-1 Protein Regulates the Induction of Autophagy Downstream of IRE1/XBP1 Pathway
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DOI：
10.1074/jbc.m112.363911
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发表时间：
2012-08-24
影响因子：
4.8
通讯作者：
Puglielli, Luigi
中科院分区：
文献类型：
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作者：
Pehar, Mariana;Jonas, Mary Cabell;Puglielli, Luigi
未折叠蛋白质反应的主要功能之一是确保处理在内质网（ER）腔中积累的大蛋白质聚集体，同时至少在非致死水平的ER应激下避免细胞死亡。当严格控制时，自噬依赖性ER相关降解（ERAD（II））允许细胞从蛋白质聚集体的瞬时积累中恢复;然而，当不受控制时，它可能是有害的，并导致自噬性细胞死亡/2型细胞死亡。在这里，我们发现IRE 1/XBP 1通过激活ER膜转运蛋白SLC 33 A1/AT-1来控制未折叠蛋白应答期间自噬/ERAD（II）的诱导，这确保了乙酰辅酶A持续供应到ER的内腔中。诱导AT-1的失败导致广泛的自噬性细胞死亡。从机制上讲，自噬过程的调节涉及Atg 9A的N-β-赖氨酸乙酰化。
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-epsilon-lysine acetylation of Atg9A.