Abstract
AbstractMicropeptides encoded by short open reading frames (sORFs) within long noncoding RNAs (lncRNAs) are beginning to be discovered and characterized as regulators of biological and pathological processes. Here, we find that lncRNA Dleu2 encodes a 17-amino-acid micropeptide, which we name Dleu2-17aa, that is abundantly expressed in T cells. Dleu2-17aa promotes inducible regulatory T (iTreg) cell generation by interacting with SMAD Family Member 3 (Smad3) and enhancing its binding to the Foxp3 conserved non-coding DNA sequence 1 (CNS1) region. Importantly, the genetic deletion of Dleu2-17aa in mice by start codon mutation impairs iTreg generation and worsens experimental autoimmune encephalomyelitis (EAE). Conversely, the exogenous supplementation of Dleu2-17aa relieves EAE. Our findings demonstrate an indispensable role of Dleu2-17aa in maintaining immune homeostasis and suggest therapeutic applications for this peptide in treating autoimmune diseases.
Funder
National Natural Science Foundation of China Original Exploration Program
MOST | National Key Research and Development Program of the Ministry of Science and Technology
MOST | National Natural Science Foundation of China
Clinical Research Plan of Shanghai Shenkang Hospital Development Center
SJTU Trans-med Awards Research
Integrated innovation fund of Shanghai Jiao Tong University
Experimental Animal Research Project of "Sientific and Technological Innovation Action Plan"
Shanghai Action Plan for Science, Technology and Innovation
Innovative Research Team of High-level Local University in Shanghai
Publisher
Springer Science and Business Media LLC
Subject
Genetics,Molecular Biology,Biochemistry