Key Points

RNF215 is upregulated by viral infection in human macrophages.

RNF215 inhibits the production of IFN-β via blocking NF-κB p65 activation.

The expression of RNF215 is negatively correlated with IFN-β in patients with SLE.

Visual AbstractAbstract

Germline-encoded pattern recognition receptors (PRRs) recognize molecules frequently found in pathogens (pathogen-associated molecular patterns [PAMPs]) during viral infection. This process induces production of IFNs, leading to expression of IFN-stimulated genes to establish a cellular antiviral state against viral infection. However, aberrant activation of the IFN system may cause immunopathological damage and systemic autoimmune diseases such as systemic lupus erythematosus. Stringent control of IFN signaling activation is critical for maintaining homoeostasis of the immune system; yet, the mechanisms responsible for its precise regulation remain to be elucidated. In this study, we identified that ring finger protein 215 (RNF215), a zinc finger protein, was upregulated by viral infection in human macrophages. In addition, we demonstrated that RNF215 inhibited the production of type I IFNs at least in part via interacting with p65, a subunit of NF-κB, and repressed the accumulation of NF-κB in the promoter region of IFNB1. Moreover, we found that the expression of RNF215 negatively correlated with type I IFNs in patients with systemic lupus erythematosus, indicating that RNF215 plays an important role in the pathogenesis of autoimmune diseases. Collectively, our data identified RNF215 as a key negative regulator of type I IFNs and suggested RNF215 as a potential target for intervention in diseases with aberrant IFN production.

Footnotes

This work was supported by grants from the Projects of International Cooperation and Exchanges of the National Natural Science Foundation of China (81820108025), the National Natural Science Foundation of China (81870960, 81971146, 82071352, 82171675, 81571992), Guangdong Marine Economy Development Special Project (GDNRC[2022]35), Guangdong Basic and Applied Basic Research Foundation (2019A1515010937, 2022A1515011156), the Natural Science Foundation of Hunan Province, China (2020JJ5562), and the National Mega Project on Major Infectious Disease Prevention (2017ZX10103011).

The online version of this article contains supplemental material.

Abbreviations used in this article:

CARDcaspase activation and recruitment domainChIPchromatin immunoprecipitationco-IPcoimmunoprecipitationHAUhemagglutinating unitsIKKεIκB kinase εIRF3IFN regulatory factor 3ISGIFN-stimulated geneISREIFN-stimulated response elementLucLuciferaseMAVSmitochondrial antiviral signaling proteinMDA5melanoma differentiation-associated gene 5PAMPpathogen-associated molecular patternPRRpattern recognition receptorQRT-PCRquantitative real-time PCRRNF215ring finger protein 215RIG-Iretinoic acid-inducible gene IRLRretinoic acid-inducible gene I–like receptorsiRNAsmall interfering RNASeVSendai virusSLEsystemic lupus erythematosusTBK1TANK binding kinase 1VSVvesicular stomatitis virusReceived May 11, 2022.Accepted September 14, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.