Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23–Th17 pathway

Abstract

Ro52/Trim21 is targeted as an autoantigen in systemic lupus erythematosus and Sjögren's syndrome. Polymorphisms in the Ro52 gene have been linked to these autoimmune conditions, but the molecular mechanism by which Ro52 may promote development of systemic autoimmune diseases has not been explored. To address this issue, we generated Ro52-null mice (Ro52−/−), which appear phenotypically normal if left unmanipulated. However, Ro52−/− mice develop severe dermatitis extending from the site of tissue injury induced by ear tags. The affected mice further develop several signs of systemic lupus with hypergammaglobulinemia, autoantibodies to DNA, proteinuria, and kidney pathology. Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17). Loss of IL-23/IL-17 by genetic deletion of IL-23/p19 in the Ro52−/− mice conferred protection from skin disease and systemic autoimmunity. These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and systemic autoimmunity through the IL-23–Th17 pathway.

TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity

“…The IFN-γ induction of TRIM21 expression was in agreement with previous studies (Carthagena et al, 2009;Espinosa et al, 2009). TRIM21 has an acknowledged role in regulating type I IFN responses (Higgs et al, 2008;Espinosa et al, 2009;Yoshimi et al, 2009;McEwan et al, 2013;Zhang et al, 2013). In one mechanism, TRIM21 has been reported to cause IKKβ degradation most likely through autophagy, based on its 3-methyladenine protection and LC3 localization (Niida et al, 2010).…”

“…TRIM21, an autoantigen associated with Sjögren syndrome and systemic lupus erythematosus, suppresses type I IFN response (Higgs et al, 2008;Espinosa et al, 2009;Yoshimi et al, 2009;Zhang et al, 2013), albeit this has been ascribed to proteasomal degradation of IRF3 (Higgs et al, 2008) and IRF7 (Higgs et al, 2010). Nevertheless, type I IFN can also be activated by NF-kB, and autophagy has been implicated in degradation of the upstream NF-kB activating kinase, IKKβ (Niida et al, 2010).…”

“…It has been proposed that TRIM21 can suppress type I IFN response (Higgs et al, 2008;Espinosa et al, 2009;Yoshimi et al, 2009;Zhang et al, 2013), albeit an activation effect (McEwan et al, 2013), has also been reported. The proposed mechanism for negative regulation of IRF3 is mainly focused on proteasomal degradation of IRF3 (Saitoh et al, 2006;Higgs et al, 2008).…”

Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β

“…For example, TRIM25 promotes K63 ubiquitination of RIG-I, which has been shown to be critical to activate viral innate immunity (43). TRIM30α inhibits toll like receptor (TLR)-mediated activation of NF-κβ by targeting TAB2 and TAB3 for degradation (42), and TRIM21 has been shown to inhibit several IFN response factors (IRF) (44,45). With regard to innate immunity, TRIM27 was shown to interact with and inhibit several IKK family members and TBK1 (TRAF family member-associated NF-κβ activator binding kinase), leading to inhibition of TLR activation of NF-κβ and IRF3 (46).…”

Fas-associated Death Domain (FADD) and the E3 Ubiquitin-Protein Ligase TRIM21 Interact to Negatively Regulate Virus-induced Interferon Production

“…Although TRIM21-mediated ubiquitination of p27 and IRF7 leads to degradation, IRF8 activity is enhanced after ubiquitination by TRIM21. Studies in TRIM21-deficient mice suggest that TRIM21 is part of a negative feedback loop for cytokines (35,36). TRIM21-deficient splenocytes produced increased amounts of inflammatory cytokines, including type I interferons, when stimulated with CpG.…”