GGNBP2 regulates MDA5 sensing triggered by self double stranded RNA following loss of ADAR1 editing

Adenosine-to-Inosine (A-to-I) editing of double stranded RNA (dsRNA) is an essential modifier of dsRNA immunogenicity. Loss of Adenosine deaminase acting on RNA 1 (ADAR1), or its A-to-I editing activity, triggers a lethal MDA5-dependent autoinflammatory response to endogenous unedited dsRNA. We performed a genome-wide suppressor screen to map the genetic landscape regulating the response to a loss of ADAR1 mediated A-to-I editing. This identified that the interacting proteins GGNBP2, CNOT10 and CNOT11 regulate immunogenic sensing following loss of A-to-I editing. GGNBP2 acts between transcription and cytoplasmic MDA5 sensing. Loss of GGNBP2 modified the distribution of dsRNA within cells, reducing the cytoplasmic dsRNA load and preventing induction of type I IFN and lethal autoinflammation. GGNBP2, CNOT10 and CNOT11 are novel regulators of the cellular response to unedited dsRNA.