Selective export of autotaxin from the endoplasmic reticulum

Lin Lyu,Baolu Wang,Chaoyang Xiong,Xiaotian Zhang,Xiaoyan Zhang,Junjie Zhang

doi:10.1074/jbc.m116.774356

Lin Lyu, Baolu Wang + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m116.774356

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Abstract

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.

Highlights

Autotaxin (ATX) or ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) is a secretory glycoprotein and functions as the key enzyme for lysophosphatidic acid generation
ATX is a secretory glycoprotein with lyso-PLD activity and functions as the key enzyme in the generation of lysophosphatidic acid (LPA)
We demonstrated that a di-phenylalanine (Phe838/Phe-839) motif in the ATX C-terminal region functioned as an endoplasmic reticulum (ER) export signal

Summary

Present address

Adaptor proteins or transmembrane receptors are required in ER export of other proteins, to mediate efficient linkage of the cargo to the coat complex. The p24 family proteins are type I membrane proteins, recycled between ER and Golgi apparatus, and act as cargo receptors responsible for exit of selective cargoes from the ER. It has been reported that p24 family proteins can recognize ER lumen-localized glycosylphosphatidylinositol-anchored proteins (GPI-APs) and act as cargo receptors for correctly remodeled GPI-APs to be sorted into COPII vesicles efficiently [28] in a Sec24C/D-dependent manner [29]. A di-hydrophobic (Phe-838/Phe-839) motif in the C-terminal region of human ATX was identified as the protein sorting signal to meditate the interaction between ATX and p23.

Results

Discussion

Experimental procedures