A peptide encoded by pri-miRNA-31 represses autoimmunity by promoting T_reg differentiation

Recent evidence has revealed that small polypeptides (containing fewer than 100 amino acids) can be translated from noncoding RNAs (ncRNAs), which are usually defined as RNA molecules that do not encode proteins. However, studies on functional products translated from primary transcripts of microRNA (pri-miRNA) are quite limited. Here, we describe a peptide termed miPEP31 that is encoded by pri-miRNA-31. miPEP31 is highly expressed in Foxp3⁺ regulatory T cells (T_regs) and significantly promotes the differentiation of T_regs without affecting their inhibitory ability. Our results show that miPEP31 is a cell-penetrating peptide both in vitro and in vivo. miPEP31 downregulates miR-31 expression, enhances peripheral T_reg induction, and dramatically suppresses experimental autoimmune encephalomyelitis. Mechanistically, we show that miPEP31 acts as a transcriptional repressor inhibiting the expression of miRNA-31, a negative regulator of T_regs. Our results reveal an indispensable role of miPEP31 in maintaining immune homeostasis by promoting T_reg differentiation and also present a potential therapeutic peptide for modulating miRNA expression and treating autoimmune diseases.