Lyu Lin, Wang Baolu, Xiong Chaoyang, Zhang Xiaotian, Zhang Xiaoyan, Zhang Junjie
From the Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
From the Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China
J Biol Chem. 2017 Apr 28;292(17):7011-7022. doi: 10.1074/jbc.M116.774356. Epub 2017 Mar 15.
Autotaxin (ATX) or ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) is a secretory glycoprotein and functions as the key enzyme for lysophosphatidic acid generation. The mechanism of ATX protein trafficking is largely unknown. Here, we demonstrated that p23, a member of the p24 protein family, was the protein-sorting receptor required for endoplasmic reticulum (ER) export of ATX. A di-phenylalanine (Phe-838/Phe-839) motif in the human ATX C-terminal region was identified as a transport signal essential for the ATX-p23 interaction. Knockdown of individual Sec24 isoforms by siRNA revealed that ER export of ATX was impaired only if Sec24C was down-regulated. These results suggest that ATX is selectively exported from the ER through a p23, Sec24C-dependent pathway. In addition, it was found that AKT signaling played a role in ATX secretion regulation to facilitate ATX ER export by enhancing the nuclear factor of activated T cell-mediated p23 expression. Furthermore, the di-hydrophobic amino acid motifs (FY) also existed in the C-terminal regions of human ENPP1 and ENPP3. Such a p23, Sec24C-dependent selective ER export mechanism is conserved among these ENPP family members.
自分泌运动因子（ATX）或胞外核苷酸焦磷酸酶/磷酸二酯酶2（ENPP2）是一种分泌性糖蛋白，作为溶血磷脂酸生成的关键酶发挥作用。ATX蛋白运输的机制在很大程度上尚不清楚。在此，我们证明p24蛋白家族成员p23是ATX从内质网（ER）输出所需的蛋白质分选受体。人ATX C末端区域的双苯丙氨酸（Phe-838/Phe-839）基序被确定为ATX与p23相互作用所必需的转运信号。通过小干扰RNA（siRNA）敲低单个Sec24亚型表明，只有当Sec24C被下调时，ATX的内质网输出才会受损。这些结果表明，ATX通过p23、Sec24C依赖的途径从内质网中被选择性输出。此外，还发现AKT信号传导在ATX分泌调节中发挥作用，通过增强活化T细胞核因子介导的p23表达来促进ATX的内质网输出。此外，人ENPP1和ENPP3的C末端区域也存在双疏水氨基酸基序（FY）。这种p23、Sec24C依赖的选择性内质网输出机制在这些ENPP家族成员中是保守的。
