Volume 33, No 7, Jul 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 7, July 2023: 497-515   |  Open Access

ORIGINAL ARTICLES

Disruption of ER ion homeostasis maintained by an ER anion channel CLCC1 contributes to ALS-like pathologies

Liang Guo^1,2,3,4,? , Qionglei Mao^5,6,? , Ji He^7,? , Xiaoling Liu^4,8 , Xuejiao Piao^1,2,3,4 , Li Luo^3,9 , ^5,10,11,* , Hanzhi Yu² , Qiang Song³ , Bailong Xiao^1,4,8 , Dongsheng Fan^7,12,* , Zhaobing Gao^5,6,* , Yichang Jia^1,3,4,9,*

¹Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, China
²School of Life Sciences, Tsinghua University, Beijing, China
³School of Medicine, Tsinghua University, Beijing, China
⁴IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China
⁵CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia and Medica, Chinese Academy of Sciences, Shanghai, China.
⁶University of Chinese Academy of Sciences, Beijing, China
⁷Department of Neurology, Peking University Third Hospital, Beijing, China
⁸School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
⁹Tsinghua Laboratory of Brain and Intelligence, Beijing, China
¹⁰School of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
¹¹School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang, China
¹²Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
^?These authors contributed equally: Liang Guo, Qionglei Mao, Ji He
Correspondence: ()Dongsheng Fan(dsfan2010@aliyun.com)Zhaobing Gao(zbgao@simm.ac.cn)Yichang Jia(yichangjia@tsinghua.edu.cn)

Although anion channel activities have been demonstrated in sarcoplasmic reticulum/endoplasmic reticulum (SR/ER), their molecular identities and functions remain unclear. Here, we link rare variants of Chloride Channel CLIC Like 1 (CLCC1) to amyotrophic lateral sclerosis (ALS)-like pathologies. We demonstrate that CLCC1 is a pore-forming component of an ER anion channel and that ALS-associated mutations impair channel conductance. CLCC1 forms homomultimers and its channel activity is inhibited by luminal Ca2+ but facilitated by phosphatidylinositol 4,5-bisphosphate (PIP2). We identified conserved residues D25 and D181 in CLCC1 N-terminus responsible for Ca2+ binding and luminal Ca2+-mediated inhibition on channel open probability and K298 in CLCC1 intraluminal loop as the critical PIP2-sensing residue. CLCC1 maintains steady-state [Cl–]ER and [K+]ER and ER morphology and regulates ER Ca2+ homeostasis, including internal Ca2+ release and steady-state [Ca2+]ER. ALS-associated mutant forms of CLCC1 increase steady-state [Cl–]ER and impair ER Ca2+ homeostasis, and animals with the ALS-associated mutations are sensitized to stress challenge-induced protein misfolding. Phenotypic comparisons of multiple Clcc1 loss-of-function alleles, including ALS-associated mutations, reveal a CLCC1 dosage dependence in the severity of disease phenotypes in vivo. Similar to CLCC1 rare variations dominant in ALS, 10% of K298A heterozygous mice developed ALS-like symptoms, pointing to a mechanism of channelopathy dominant-negatively induced by a loss-of-function mutation. Conditional knockout of Clcc1 cell-autono

https://doi.org/10.1038/s41422-023-00798-z

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