1-P-053
ALSに関連する変異ubiquilin 2はオートファジー・リソソーム系タンパク質分解を障害する
ALS-associated mutant ubiquilin 2 impairs protein degradation via autophagy-lysosome system
〇井寺 晃子1、関 貴弘1,2、佐藤 正寛2、倉内 祐樹1,2、香月 博志1,2
Akiko Idera1, Takahiro Seki1,2, Masahiro Sato2, Yuki Kurauchi1,2, Hiroshi Katsuki1,2
1熊本大・薬・薬物活性、2熊本大・院生命(薬)・薬物活性
1Dept. Chemico-Pharmacol. Sci., Grad. Sch. Pharm. Sci., Kumamoto Univ., 2Dept. Chemico-Pharmacol. Sci., Grad. Sch. Pharm. Sci., Kumamoto Univ.
Ubiquilin 2 (UBQLN2) has ubiquitin-like and ubiquitin-associated domains and regulates protein degradation systems. Missense mutations of UBQLN2 have been recently identified as causal genes of familial amyotrophic lateral sclerosis (ALS). ALS-associated mutant UBQLN2 has been reported to impair protein degradation via ubiquitin-proteasome system. In the present study, we investigated how mutant UBQLN2 affects protein degradation via autophagy-lysosome system, which is classified into three pathways, macroautophagy (MA), microautophagy (mA) and chaperone-mediated autophagy (CMA). We first assessed mA/CMA activity using AD293 cells stably expressing GAPDH-HT, a marker of mA/CMA activity. Overexpressed wild-type UBQLN2 decreased mA/CMA activity, and the overexpression of mutant UBQLN2 exacerbated the decrease of mA/CMA activity. Experiments using rapamycin and mycophenolic acid, activators of mA and CMA, respectively, revealed that CMA was mainly impaired by wild-type and mutant UBQLN2. As for MA, autophagic flux assay using bafilomycin A1, a lysosome inhibitor, revealed that mutant UBQLN2 decreased MA activity in AD293 cells. These findings suggest that ALS-associated mutant UBQLN2 impairs MA and CMA and disturbs protein quality control. This disturbance would be related to the pathogenesis of ALS caused by UBQLN2 mutation.