Nucleoporin POM121 signals TFEB-mediated autophagy via activation of SIGMAR1/sigma-1 receptor chaperone by pridopidine

被引:39
作者
Wang, Shao-Ming [1 ,2 ,3 ,4 ]
Wu, Hsiang-En [1 ]
Yasui, Yuko [1 ]
Geva, Michal [5 ]
Hayden, Michael [5 ,6 ]
Maurice, Tangui [7 ]
Cozzolino, Mauro [8 ]
Su, Tsung-Ping [1 ]
机构
[1] NIDA, Cellular Pathobiol Sect, Integrat Neurosci Res Branch, Intramural Res Program,NIH,DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA
[2] China Med Univ, Grad Inst Biomed Sci, Taichung, Taiwan
[3] China Med Univ, Neurosci & Brain Dis Ctr, 91 Hsueh Shih Rd, Taichung 404333, Taiwan
[4] China Med Univ Hosp, Dept Neurol, 2 Yude Rd, Taichung 404333, Taiwan
[5] Prilenia Therapeut Dev Ltd, Herzliyya, Israel
[6] Univ British Columbia, BC Childrens Hosp Res Inst, Ctr Mol Med & Therapeut, Vancouver, BC, Canada
[7] Univ Montpellier, INSERM, EPHE, MMDN, Montpellier, France
[8] CNR, Inst Translat Pharmacol, Via Fosso del Cavaliere 100, I-00133 Rome, Italy
关键词
ALS/FTD; c9orf72; chaperone; KPNB1/importin beta 1; nucleocytoplasmic transport; nucleoporin POM121; pridopidine; SIGMAR1; sigma-1; receptor; TFEB; NUCLEAR-PORE COMPLEX; SIGMA-1; RECEPTOR; REPEAT EXPANSION; MOUSE MODEL; HEXANUCLEOTIDE REPEAT; C9ORF72; BINDING; DYSREGULATION; MODULATOR; ENDOCRINE;
D O I
10.1080/15548627.2022.2063003
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Macroautophagy/autophagy is an essential process for cellular survival and is implicated in many diseases. A critical step in autophagy is the transport of the transcription factor TFEB from the cytosol into the nucleus, through the nuclear pore (NP) by KPNB1/importin beta 1. In the C9orf72 subtype of amyotrophic lateral sclerosis-frontotemporal lobar degeneration (ALS-FTD), the hexanucleotide (G4C2)RNA expansion (HRE) disrupts the nucleocytoplasmic transport of TFEB, compromising autophagy. Here we show that a molecular chaperone, the SIGMAR1/Sigma-1 receptor (sigma non-opioid intracellular receptor 1), facilitates TFEB transport into the nucleus by chaperoning the NP protein (i.e., nucleoporin) POM121 which recruits KPNB1. In NSC34 cells, HRE reduces TFEB transport by interfering with the association between SIGMAR1 and POM121, resulting in reduced nuclear levels of TFEB, KPNB1, and the autophagy marker LC3-II. Overexpression of SIGMAR1 or POM121, or treatment with the highly selective and potent SIGMAR1 agonist pridopidine, currently in phase 2/3 clinical trials for ALS and Huntington disease, rescues all of these deficits. Our results implicate nucleoporin POM121 not merely as a structural nucleoporin, but also as a chaperone-operated signaling molecule enabling TFEB-mediated autophagy. Our data suggest the use of SIGMAR1 agonists, such as pridopidine, for therapeutic development of diseases in which autophagy is impaired.
引用
收藏
页码:126 / 151
页数:26
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