Thousands of long non-coding RNAs (lncRNAs) are encoded in mammalian genomes, yet the majority of them remain uncharacterized. In previous studies, we identified a mouse lncRNA of unknown function called U90926, expressed in activated macrophages. Here, we functionally characterized this gene in vitro and in vivo. Analysis of U90926 RNA levels revealed minimal expression across multiple tissues at steady state. However, the expression of this gene is highly induced in myeloid cells by toll-like receptor activation, in a p38 MAP kinase and MYD88-dependent manner. To study the function of U90926, we generated U90926-deficient (U9-KO) mice. Surprisingly, we found minimal effects of U90926 deficiency on gene expression in cultured macrophages. Given this lack of a macrophage-intrinsic effect, we investigated the subcellular localization of U90926 transcript and its protein-coding potential. We found that U90926 RNA localizes to the cytosol, associates with ribosomes, and contains an open reading frame that encodes a novel protein (termed U9-ORF). U9-ORF contains an ER signal peptide sequence, traffics to the Golgi, and is secreted from the cell. In vivo, the LPS endotoxemia model showed that U9-KO mice exhibited increased sickness responses and mortality in comparison with WT mice. Mechanistically, serum levels of IL-6 were elevated at in U9-KO mice compared with WT, and IL-6 neutralization improved sepsis outcome in U9-KO mice. Taken together, these results suggest that the protective effect of U90926 expression during endotoxic shock is orchestrated by regulating IL-6 levels, likely mediated by the paracrine and/or endocrine actions of the novel U9-ORF peptide secreted by activated myeloid cells.

Supported by grants from the NIH (R21AI151116 to DNK and P30GM118228 to Dr. Ralph Budd).

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