SMURF1 activates the cGAS/STING/IFN-1 signal axis by mediating YY1 ubiquitination to accelerate the progression of lupus nephritis

Abstract

Aggravated endoplasmic reticulum stress (ERS) and apoptosis in podocytes play an important role in lupus nephritis (LN) progression, but its mechanism is still unclear. Herein, the role of SMURF1 in regulating podocytes apoptosis and ERS during LN progression were investigated. MRL/lpr mice was used as LN model in vivo. HE staining was performed to analyze histopathological changes. Mouse podocytes (MPC5 cells) were treated with serum IgG from LN patients (LN-IgG) to construct LN model in vitro. CCK8 assay was adopted to determine the viability. Cell apoptosis was measured using flow cytometry and TUNEL staining. The interactions between SMURF1, YY1 and cGAS were analyzed using ChIP and/or dual-luciferase reporter gene and/or Co-IP assays. YY1 ubiquitination was analyzed by ubiquitination analysis. Our results found that SMURF1, cGAS and STING mRNA levels were markedly increased in serum samples of LN patients, while YY1 was downregulated. YY1 upregulation reduced LN-IgG-induced ERS and apoptosis in podocytes. Moreover, SMURF1 upregulation reduced YY1 protein stability and expression by ubiquitinating YY1 in podocytes. Rescue studies revealed that YY1 knockdown abrogated the inhibition of SMURF1 downregulation on LN-IgG-induced ERS and apoptosis in podocytes. It was also turned out that YY1 alleviated podocytes injury in LN by transcriptional inhibition cGAS/STING/IFN-1 signal axis. Finally, SMURF1 knockdown inhibited LN progression in vivo. In short, SMURF1 upregulation activated the cGAS/STING/IFN-1 signal axis by regulating YY1 ubiquitination to facilitate apoptosis in podocytes during LN progression.

Keywords:

• Lupus nephritis
• endoplasmic reticulum stress
• SMURF1
• YY1
• cGAS/STING/IFN-1 signal axis

Authors’ contributions

Xiaoyan Li: Conceptualization; Methodology; Validation; Writing – Original Draft; Sisi Tao: Formal analysis; Investigation; Zhiquan Xu: Resources; Data Curation; Yi Ren: Visualization; Wei Xiang: Supervision; Xiaojie He: Writing – Review and Editing; Project administration; Funding acquisition.

Ethics approval and consent to participate

The study was authorized by the Ethics Committee of Hainan women and Children’s medical center before enrollment of patients. All participants signed informed consent. All procedures involving animals were performed strictly in accordance to the guide for the Care and Use of Laboratory Animals, under the approval by Hainan women and Children’s medical center. Approval number: [Ethical Review No. 118 of 2022].

Availability of data and materials

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that there is no conflict of interest.

Consent for publication

The informed consent was obtained from study participants.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors express their gratitude to for his help for directing our article. This work was supported by grants from 2022JJ30064, 2022JJ70048, Natural Science Foundation of Hunan Province; 2021SK53201, Hunan Province clinical medical technology innovation guide project; S2022JJKWLH0255, Hainan Province science and health joint project; 821RC1130, Natural Science Foundation of Hainan Province; ZDYF2021SHFZ088, Key R&D Plan of Hainan Province