A novel lncRNA U90926 increases susceptibility to endotoxic shock Bristy Sabikunnahar, Stella Varnum, Sydney Caldwell, Dimitry N. Krementsov Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT 05405, USA. Emerging studies have identified thousands of long non-coding RNAs (lncRNAs) in mammalian genomes that regulate numerous cellular processes including innate immune cell effector function. We have identified a novel mouse lncRNA of unknown function called U90926, whose expression in activated macrophages was highly dependent on p38 MAP kinase (MAPK). Here, we further functionally characterized this gene in both in vitro and in vivo models. Analysis of U90926expression revealed no expression across multiple tissues, including unstimulated macrophages. However, we have found that the expression of this gene is highly inducible in myeloid cells by LPS stimulation and other toll-like receptors (TLRs) agonists, in a p38 MAPK- and MYD88-dependent manner. To study the function of U90926, we generated U90926-knockout (U9-KO) mice using CRISPR-Cas9 technology. Our in vivo LPS endotoxemia model showed that U9-KO mice exhibited increased sickness responses and increased mortality in comparison with WT mice, suggesting that U90926 has a protective role in septic shock. Surprisingly, we found minimal effects of U90926 deficiency on gene expression in cultured LPS-activated BMDM. Given the lack of intrinsic effect of U90926 on gene expression, we investigated the subcellular localization of U90926 transcript and its protein-coding potential. We found that U90926 lncRNA localizes in the cytosol and associates with ribosomes. Furthermore, we determined that U90926 contains an open reading frame that encodes a novel peptide, which contains an ER signal peptide sequence, traffics to the Golgi, and is secreted from the cell. Taken together, these results suggest that the protective response of U90926 during endotoxic shock is orchestrated by the paracrine and/or endocrine actions of U90926 novel peptide, secreted by activated myeloid cells.