Regulation of mRNA stability contributes to the function of innate lymphoid cells in various diseases

Abstract

Innate lymphoid cells (ILCs) are important subsets of innate immune cells that regulate mucosal immunity. ILCs include natural killer cells, innate lymphoid cells-1 (ILC1s), ILC2s, and ILC3s, which have extremely important roles in the immune system. In this review, we summarize the regulation of mRNA stability mediated through various factors in ILCs (e.g., cytokines, RNA-binding proteins, non-coding RNAs) and their roles in mediating functions in different ILC subsets. In addition, we discuss potential therapeutic targets for diseases such as chronic obstructive pulmonary disease, cancer, and pulmonary fibrosis by regulation of mRNA stability in ILCs, which may provide novel directions for future clinical research.

Keywords: ILCs; RBPs; cytokines; mRNA stability; non-coding RNA.

Figure 1

Regulation of the stability of IFN-γ mRNA in NK cells through p38 MAPK and PKC signal-transduction pathways. For clarity, these posttranscriptional regulators are not necessarily placed at the correct cell site. IL-12 and IL-18 can enhance the stability of IFN-γ mRNA in NK cells through the p38 MAPK pathway, which may phosphorylate unknown RBPs to result in decreased RNA-binding affinity and then decreased deadenylation. TGF-β inhibits the stability of IL-18-induced IFN-γ mRNA. IL-18 may inhibit TTP mRNA and affect the stability of IFN-γ mRNA through the p38 MAPK pathway, which may phosphorylate TTP. This phosphorylation results in the decreased RNA-binding affinity of TTP, which can trigger deadenylation of IFN-γ mRNA by recruiting cytoplasmic deadenylase. However, TGF-β can upregulate TTP transcription specifically through the Smad pathway. Smad proteins downstream of TGF-β receptors can mediate a stimulatory effect by binding the SBE of the TTP promoter (45), thereby repressing expression of IL-18-induced IFN-γ mRNA through TTP-induced destabilization. A similar TTP-related mechanism may be found in IL-33-stimulated NK cells. IL-2 and IL-12 may affect the stability of cytoplasmic IFN-γ mRNA and stability of the nuclear-processed form of IFN-γ mRNA through PKC-dependent polyadenylation in NK cells. In addition, IL-12 mediates nuclear shuttling whereas IL-2 mediates nuclear retention, which may be related to AREs, but the specific mechanism requires further investigation. Solid arrows indicate confirmed mechanisms. Dashed arrows indicate possible mechanisms that need further verification. Molecular interactions and all abbreviations are explained in the text.