Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
Int J Mol Sci. 2021 Jul 7;22(14):7311. doi: 10.3390/ijms22147311.
The members of the ZC3H12/MCPIP/Regnase family of RNases have emerged as important regulators of inflammation. In contrast to Regnase-1, -2 and -4, a thorough characterization of Regnase-3 (Reg-3) has not yet been explored. Here we demonstrate that Reg-3 differs from other family members in terms of NYN/PIN domain features, cellular localization pattern and substrate specificity. Together with Reg-1, the most comprehensively characterized family member, Reg-3 shared IL-6, IER-3 and Reg-1 mRNAs, but not IL-1β mRNA, as substrates. In addition, Reg-3 was found to be the only family member which regulates transcript levels of TNF, a cytokine implicated in chronic inflammatory diseases including psoriasis. Previous meta-analysis of genome-wide association studies revealed Reg-3 to be among new psoriasis susceptibility loci. Here we demonstrate that Reg-3 transcript levels are increased in psoriasis patient skin tissue and in an experimental model of psoriasis, supporting the immunomodulatory role of Reg-3 in psoriasis, possibly through degradation of mRNA for TNF and other factors such as Reg-1. On the other hand, Reg-1 was found to destabilize Reg-3 transcripts, suggesting reciprocal regulation between Reg-3 and Reg-1 in the skin. We found that either Reg-1 or Reg-3 were expressed in human keratinocytes in vitro. However, in contrast to robustly upregulated Reg-1 mRNA levels, Reg-3 expression was not affected in the epidermis of psoriasis patients. Taken together, these data suggest that epidermal levels of Reg-3 are negatively regulated by Reg-1 in psoriasis, and that Reg-1 and Reg-3 are both involved in psoriasis pathophysiology through controlling, at least in part different transcripts.
ZC3H12/MCPIP/Regnase 家族的 RNases 成员已成为炎症的重要调节因子。与 Regnase-1、-2 和 -4 不同，Regnase-3（Reg-3）的全面特征尚未得到探索。在这里，我们证明 Reg-3 在 NYN/PIN 结构域特征、细胞定位模式和底物特异性方面与其他家族成员不同。与最全面表征的家族成员 Reg-1 一起，Reg-3 共享 IL-6、IER-3 和 Reg-1 mRNA，但不共享 IL-1β mRNA 作为底物。此外，发现 Reg-3 是唯一调节 TNF 转录水平的家族成员，TNF 是一种细胞因子，与包括银屑病在内的慢性炎症性疾病有关。先前对全基因组关联研究的荟萃分析显示 Reg-3 是新的银屑病易感性基因座之一。在这里，我们证明 Reg-3 转录物水平在银屑病患者皮肤组织和银屑病实验模型中增加，支持 Reg-3 在银屑病中的免疫调节作用，可能通过降解 TNF 和其他因子（如 Reg-1）的 mRNA。另一方面，发现 Reg-1 可使 Reg-3 转录物不稳定，表明 Reg-3 和 Reg-1 在皮肤中存在相互调节。我们发现，无论是 Reg-1 还是 Reg-3，在体外的人角质形成细胞中都有表达。然而，与 Reg-1 mRNA 水平的强烈上调相反，银屑病患者表皮中 Reg-3 的表达不受影响。综上所述，这些数据表明，在银屑病中，Reg-1 负调节表皮中 Reg-3 的水平，并且 Reg-1 和 Reg-3 都通过控制至少部分不同的转录物参与银屑病的病理生理学。
