Golgi body is regulated by COPI vesicle transport via Scyl1 methylation under ER stress

抄録

Cumulative evidences have shown the importance of ER-stress in pathology of neurodegenerative diseases, such as Alzheimer's disease, Amyotrophic lateral sclerosis, etc. To elucidate the pathogenesis of neurodegenerative diseases from the viewpoint of ER-stress, we screened the altered genes in SK-N-SH cells under the condition of tunicamycin-induced ER-stress by the gene fishing method. As the result, we found that Protein arginine N-methyltransferase 1 (PRMT1) is up-regulated in SK-N-SH cells under ER-stress. Based on this result, we examined the effects of PRMT1 knockdown on the ER-stress related pathway and organelle, and found that PRMT1 knockdown cells showed the abnormal Golgi formation and increased UPR. To elucidate the mechanism of these alterations, we screened the methylated proteins as substrates of PRMT1 under ER-stress condition by immunoprecipitation-mass spectroscopy, and identified Scy1-like protein 1 (Scyl1). Scyl1, a member of the Scy1-like family of catalytically inactive protein kinases, was recently reported to function in retrograde COPI-mediated intracellular transport. Interestingly, Scyl1 has also been identified as a gene product that is lost in an animal model of motor neuron disease, the muscle-deficient mouse. In the motor neuron of the above model animal, the protein circulation system between ER and Golgi apparatus was abnormal due to dysfunction of COPI transport. In consequence, UPR may be accerelated. Thus, we present the effect of Scyl1 arginine methylation on the COPI vesicle transport. This study provides novel insights into the pathogenesis of neurodegenerative diseases caused by ER stress.