Interaction between RNF4 and SART3 is associated with the risk of schizophrenia
Ying Cheng,
Xi Chen,
Xiao Qing Zhang,
Pei Jun Ju,
Wei Di Wang,
Yu Fang,
Guan Ning Lin,
Dong Hong Cui
Affiliations
Ying Cheng
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
Xi Chen
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
Xiao Qing Zhang
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
Pei Jun Ju
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Wei Di Wang
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Division of Imaging, Computational and Systems Biomedicine, School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
Yu Fang
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
Guan Ning Lin
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Division of Imaging, Computational and Systems Biomedicine, School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China; Corresponding author. Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, TEL, China.
Dong Hong Cui
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China; Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China; Corresponding author. Shanghai Mental Health Center Shanghai Jiao Tong University School of Medicine Shanghai, TEL, China.
The pathogenesis of schizophrenia (SCZ) is heavily influenced by genetic factors. Ring finger protein 4 (RNF4) and squamous cell carcinoma antigen recognized by T cells 3 (SART3) are thought to be involved in nervous system growth and development via oxidative stress pathways. Moreover, they have previously been linked to SCZ. Yet the role of RNF4 and SART3 in SCZ remains unclear. Here, we investigated how these two genes are involved in SCZ by studying their variants observed in patients. We first observed significantly elevated mRNA levels of RNF4 and SART3 in the peripheral blood in both first-episode (n = 30) and chronic (n = 30) SCZ patients compared to controls (n = 60). Next, we targeted-sequenced three single nucleotide polymorphisms (SNPs) in SART3 and six SNPs in RNF4 for association with SCZ using the genomic DNA extracted from peripheral blood leukocytes from SCZ participants (n = 392) and controls (n = 572). We observed a combination of SNPs that included rs1203860, rs2282765 (both in RNF4), and rs2287550 (in SART3) was associated with increased risk of SCZ, suggesting common pathogenic mechanisms between these two genes. We then conducted experiments in HEK293T cells to better understand the interaction between RNF4 and SART3. We observed that SART3 lowered the expression of RNF4 through ubiquitination and downregulated the expression of nuclear factor E2-related factor 2 (NRF2), a downstream factor of RNF4, implicating the existence of a possible shared regulatory mechanism for RNF4 and SART3. In conclusion, our study provides evidence that the interaction between RNF4 and SART3 contributes to the risk of SCZ. The findings shed light on the underlying molecular mechanisms of SCZ and may lead to the development of new therapies and interventions for this disorder.
