Unfolded protein response gene GADD34 is overexpressed in rheumatoid arthritis and related to the presence of circulating anti-citrullinated protein antibodies

Abstract

Growth arrest and DNA damage-inducible gene 34 (GADD34) is an inducible cofactor of protein phosphatase 1, which has an important role in the unfolded protein response. GADD34 has been shown to be necessary for type I interferon and proinflammatory cytokine production in response to viral infection in murine models. We investigate the expression of GADD34 in rheumatoid arthritis (RA), in which proinflammatory cytokines have an important pathogenic role. The objective of this study was to evaluate the potential of GADD34 expression as a biomarker in RA patients. We report a case-control study on GADD34 gene expression in peripheral blood mononuclear cells of patients (n = 75) with RA and age- and sex-matched healthy controls (n = 25). The study was approved by the relevant local ethics committees. GADD34 gene expression level in peripheral blood mononuclear cells was measured by quantitative PCR and analyzed with Mann-Whitney test. The relation between GADD34 gene overexpression and clinical or biological characteristics was analyzed with univariate and multivariate analysis. GADD34 gene expression was significantly higher in RA patients compared with healthy controls (p ≤ 0.001). Interestingly, GADD34 overexpression in PBMC of patients was related to the presence of circulating anti-citrullinated protein antibodies (p = 0.030). Data of this study strengthen the evidence of an unfolded protein response during the course of RA and provide an insight of the potential interest in GADD34 as a relevant marker for RA.

At the crossway of ER‐stress and proinflammatory responses

“…Importantly, GADD34 mRNA transcription was recently shown to be under the control of the transcription factors IRF3 and IRF7, which are induced after TLR or RLR triggering and control type‐I IFN production in most cells exposed to microbes. This previously unsuspected ATF4‐independent transcription explains why GADD34 expression is observed in most cells exposed to infection or to a proinflammatory environment . Our laboratory has also demonstrated that eIF2α dephosphorylation by the PP1‐GADD34 complex is absolutely necessary, both in vitro and in vivo , for type‐I IFN and IL‐6 production in response to VSV or Chikungunya virus infection .…”

“…BIP is also targeted during bacterial infection, for example, the cholera‐like AB 5 ‐subunit subtilase toxin can enter the ER lumen and induce degradation of BIP, activating the UPR and creating permissive conditions for bacterial replication . In several inflammatory diseases such as cutaneous systemic sclerosis, the expression of BIP and of several other ER‐stress‐related molecules, is found elevated in peripheral blood mononuclear cells , while antichaperone autoreactive antibodies titers are elevated . Interestingly, the UPR seems to have the capacity to drive proinflammatory responses independently of other immunological cues.…”

Type I Interferon Gene Response Is Increased in Early and Established Rheumatoid Arthritis and Correlates with Autoantibody Production

“…Recently, a strong association between RA and the unfolded protein response (UPR) was described (55–57), and therefore, the regulation of the transcription/translation process has been put on the spotlight of RA pathogenesis. It has been described that several regulators of the translation of proteins particularly GADD34 are associated with the UPR in RA (55); however, little attention has been put to the transcriptional process and their regulators such as IFIT1 and IFIT2 that are known to regulate the apoptotic process (58).…”

“…It has been described that several regulators of the translation of proteins particularly GADD34 are associated with the UPR in RA (55); however, little attention has been put to the transcriptional process and their regulators such as IFIT1 and IFIT2 that are known to regulate the apoptotic process (58). In this regard, we found an increased expression of these genes in the established disease phase.…”

Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis

“…PERK may therefore be considered as a therapeutic target for the treatment of osteoarthritis [105]. Broadening the scope beyond osteoarthritis, ER stress and the UPR may also play a role in the development and progression of rheumatoid arthritis [106]. …”