Degradable noncoding RNA RCoM1 mutes interferon immunity in resting macrophages Marina Aznaourova, Katharina Walther, Jonas Wehrenberg, Leon N Schulte*, # *Philipps University Marburg, Institute for Lung Research, Germany # German Center for Lung Research (DZL) Macrophages play a key role in the innate immune response to infectious agents. However, dysregulation of cytokine and interferon production by these cells can trigger severe systemic pathologies. By RNA-seq analysis of bacterially stimulated macrophages and blood samples from sepsis patients, we identified a degradable long non-coding RNA (lncRNA) which suppresses premature immune activation of resting macrophages. Inhibitor and RNA-FISH experiments revealed a c-Myc-dependent, cytoplasmic expression pattern of this lncRNA, which we termed RCoM1. Silencing of RCoM1 in human primary macrophages led to a spontaneous activation of interferon-beta and interferon-stimulated gene expression. Supporting a direct role in interferon-inducing signaling pathways, we found RCoM1 to co-sediment with TBK1 and IRF3 on glycerol density gradients. RAP-MS affinity chromatography revealed the association of RCoM1 with heat shock proteins, suggesting a chaperone-dependent regulation of the TBK1-IRF3 signaling pathway. In summary, we believe that RCoM1 is an important post-transcriptional suppressor of macrophage immunity in humans, degraded after bacterial recognition and during acute inflammatory pathologies.