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Theranostics 2022; 12(17):7289-7306. doi:10.7150/thno.76138 This issue Cite

Research Paper

C9orf72 regulates the unfolded protein response and stress granule formation by interacting with eIF2α

Wenzhong Zheng^1#, Kexin Wang^1#, Yachen Wu^1#, Ge Yan^1,3, Chi Zhang^1,3, Zhiqiang Li¹, Lianrong Wang^1,2✉, Shi Chen^1,3✉

1. Brain Center, Department of Neurosurgery, Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
2. Department of Gastroenterology, Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Disease, Taikang Center for Life and Medical Sciences, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
3. Department of Burn and Plastic Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China
#These authors contributed equally

✉ Corresponding authors: Professor Shi Chen, shichen_2021com; Professor Lianrong Wang, lianrongedu.cn

Abstract

Rationale: A C9orf72 hexanucleotide repeat expansion (GGGGCC) is the most common genetic origin of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Haploinsufficiency of C9orf72 has been proposed as a possible disease mechanism (loss-of-function mechanism). Additionally, the aberrantly activated unfolded protein response (UPR) and stress granule (SG) formation are associated with the etiopathology of both ALS and FTD. However, the molecular determinants in this pathogenesis are not well characterized.

Methods: We performed an immunoprecipitation-mass spectrometry (IP-MS) assay to identify potential proteins interacting with the human C9orf72 protein. We used C9orf72 knockout cell and rat models to determine the roles of C9orf72 in translation initiation and the stress response.

Results: Here, we show that C9orf72, which is genetically and pathologically related to ALS and FTD, interacts with eukaryotic initiation factor 2 subunit alpha (eIF2α) and regulates its function in translation initiation. C9orf72 knockout weakens the interaction between eIF2α and eIF2B5, leading to global translation inhibition. Moreover, the loss of C9orf72 results in primary ER stress with activated UPR in rat spleens, which is one of the causes of splenomegaly with inflammation in C9orf72^-/- rats. Finally, C9orf72 delays SG formation by interacting with eIF2α in stressed cells.

Conclusions: In summary, these data reveal that C9orf72 modulates translation initiation, the UPR and SG formation, which have implications for understanding ALS/FTD pathogenesis.

Keywords: C9orf72, eIF2α, translation initiation, unfolded protein response, stress granule formation

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