mascRNA alleviates STING-TBK1 signaling-mediated immune response through promoting ubiquitination of STING.

mascRNA (MALAT1-associated small cytoplasmic RNA) is a tRNA-like cytoplasmic small noncoding RNA whose function remains elusive. We previously revealed that this small RNA negatively regulates TLR4/2-triggered proinflammatory response while positively regulates TLR3-induced antiviral response. Here, we investigated whether and how mascRNA influences the stimulator of interferon genes (STING) signaling-triggered immune response. We found that overexpression of mascRNA inhibited the expression of type I interferon (IFN) genes and proinflammatory cytokines in response to cytosolic DNA stimulation; meanwhile, the abundance of STING protein and the level of phosphorylated TBK1 and STAT1 was decreased. By contrast, depletion of mascRNA potentiated the expression of type I IFNs, increased STING protein abundance, and promoted STING-mediated phosphorylation of TBK1 and STAT1 in response to DNA stimulation. In a mouse model of DNA-induced lung injury, exogenous mascRNA mitigated the antiviral response and the severity of lung inflammation. Mechanically, mascRNA was found to promote STING for K48-linked ubiquitination and degradation in macrophages both with and without cytosolic DNA stimulation. Hence, mascRNA suppresses STING-TBK1 signaling-mediated innate immunity through promoting proteasomal degradation of STING, and this tRNA-like small RNA holds promise for the treatment of certain inflammatory diseases such as COVID-19 where aberrant STING signaling drives type I IFN immunopathology.