Prion‐like Aggregation of Mitochondrial Antiviral Signaling Protein in Lupus Patients Is Associated With Increased Levels of Type I Interferon

Abstract

Objective Increased levels of Type I interferon (IFN-I) and IFN-I-regulated genes are found in patients with systemic lupus erythematosus (SLE) and may be central to its pathogenesis. The mitochondrial adaptor protein MAVS is a key regulator of IFN-I that undergoes a dramatic prion-like aggregation and self-propagates the activation signal from viral RNA to amplify downstream IFN production. We wondered if such MAVS aggregates might play a role in the sustained increased production of IFN-I in SLE. Methods Peripheral blood mononuclear cells (PBMCs) were isolated and mitochondrial extracts were prepared. MAVS aggregation was detected with semi-denatured agarose gel electrophoresis (SDD-AGE) and confirmed by immunofluorescence staining. MAVS-associated signaling proteins were analyzed by Western blot. MAVS aggregation-associated gene expression signature was analyzed by microarray. Results Blood cells from 22 of 67 SLE patients were found to have essentially all of their MAVS in a high molecular weight aggregated form. None of six rheumatoid arthritis patients and only three of 33 healthy controls had abnormal MAVS. The MAVS-aggregate positive SLE patients had significantly higher serum levels of IFN-β and significantly increased auto-antibodies against Sm and U1RNP, compared to MAVS-aggregate negative patients. Gene array data revealed a characteristic gene expression pattern in these patients, with altered expression of genes involved in IFN signaling and membrane trafficking. Conclusion Persistent MAVS aggregates may lead to increased IFN-I production and result in unmitigated signals leading to autoimmunity.

Review: Cell Death, Nucleic Acids, and Immunity

“…Interestingly, the patients with detectable cGAMP had a higher SLEDAI score than patients without activation of the pathway (70). With regard to RNA sensors, aggregation of MAVS has been demonstrated in patients with SLE which may be associated with oxidation of mtDNA (71, 72). Hasan et al (73) reported that TBK1 (a protein downstream of cGAS as well as RLR) mRNA expression was significantly increased in SLE patients, especially in monocytes.…”

Regulation of MAVS Expression and Signaling Function in the Antiviral Innate Immune Response

“…Studies have shown that persistent MAVS aggregation may be associated with the occurrence of autoimmune diseases such as systemic lupus erythematosus. Further, the sustained expression of IFN and its regulatory genes and unsuppressed signals, will eventually result in tissue damages(56).K27-linked ubiquitination by the E3 ubiquitin ligase TRIM21 also has a positive regulatory effect on MAVS. Viral infection upregulates the expression of TRIM21, thereby promoting the…”

Overexpression of miR-652-5p in new onset type 1 diabetes

“…The study of Dominguez-Gutierrez et al showed overexpression of ADAR in Systemic Lupus Erythematosus (SLE) patients [35]. In addition, decreased MARCH5 protein might account for the constant Mitochondrial Antiviral-Signaling Protein aggregations and abnormalities of type I interferon levels in SLE patients [25]. Current study did not indicate ADAR and MARCH5 as miR-652-5p targets in luciferase reporter assay.…”

“…Using the Venn's diagram (Venny 2.1.0, http://bioinfogp.cnb.csic.es/tools/venny) we identified 22 immune response genes. For further investigation 2 autoimmune related genes: Adenosine Deaminase, RNA Specific (ADAR) [24] and Membrane Associated Ring-CH Finger Protein 5 (MARCH5) [25] were selected. The sequences of miRNA bindings sites in 3'UTR of target genes were verified by PITA-Segal lab software (https://genie.weizmann.ac.il).…”