Abstract
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.
Highlights
The ZC3H12/MCPIP/Regnase family of four members (ZC3H12A-D/MCPIP1-4/Regnase1-4) was discovered quite recently
We have confirmed the importance of NYN/PIN and CCCH domains in its biological function, in contrast to other family members, mutation of crucial aspartic acid residues in the catalytic domain of Reg-3 does not result in the complete inactivation of Reg-3 ability to degrade target mRNAs
One possible explanation of this observation could be that Reg-3 itself has low RNase activity and it participates in transcript degradation by forming the complexes with other RNases
Summary
Few years later the RNase activities and the anti-inflammatory roles of ZC3H12D/MCPIP4/Reg-4 and ZC3H12B/MCPIP2/Reg-2 were reported. These proteins contain a CCCH type zinc finger responsible for their interaction with RNA. The involvement of ZC3H12D in the regulation of inflammation is suggested by its enrichment in inflamed organs such as spleen and lung as well as in lymph nodes [10] and by a sustained, upregulated levels of activated T cells [11]. It was shown that Reg-3 regulates Reg-1 level in a NYN/PIN domain-dependent manner This observation is in agreement with the results showing increased amount of Reg-1 in Zc3h12c−/− macrophages [12]. In this study we have analyzed the mechanisms involved in Reg-3 function and examined a set of inflammation-related mRNAs as its possible targets, focusing on psoriasis, where Reg-3 may control disease-relevant mediators
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