Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown

Abstract

Type I interferon (IFN) is produced when host sensors detect foreign nucleic acids, but how sensors differentiate self from nonself nucleic acids, such as double-stranded RNA (dsRNA), is incompletely understood. Mutations in ADAR1, an adenosine-to-inosine editing enzyme of dsRNA, cause Aicardi-Goutières syndrome, an autoinflammatory disorder associated with spontaneous interferon production and neurologic sequelae. We generated ADAR1 knockout human cells to explore ADAR1 substrates and function. ADAR1 primarily edited Alu elements in RNA polymerase II (pol II)-transcribed mRNAs, but not putative pol III-transcribed Alus. During the IFN response, ADAR1 blocked translational shutdown by inhibiting hyperactivation of PKR, a dsRNA sensor. ADAR1 dsRNA binding and catalytic activities were required to fully prevent endogenous RNA from activating PKR. Remarkably, ADAR1 knockout neuronal progenitor cells exhibited MDA5 (dsRNA sensor)-dependent spontaneous interferon production, PKR activation, and cell death. Thus, human ADAR1 regulates sensing of self versus nonself RNA, allowing pathogen detection while avoiding autoinflammation.

Double-Stranded RNA Sensors and Modulators in Innate Immunity

“…While some studies have suggested the possibility of ligandindependent activation of MDA5 (47), others have reported the role of endogenous dsRNAs, in particular those formed by inverted repeat Alu elements (IR-Alus), in constitutive activation of MDA5 (8). Similar IR-Alu-mediated activation was observed for wild-type MDA5 under the condition where the dsRNA-modifying enzyme ADAR1 (adenosine deaminase acting on RNA 1) is deficient (discussed below) (8,48). Recent studies showed that a chemotherapeutic agent, 5-aza-2 ′ -deoxycytidine, also activates MDA5 by upregulating endogenous retrovirus dsRNAs, leading to sterile inflammation that is beneficial for the subsequent cancer immunotherapies (49,50).…”

“…Accumulating evidence suggests that PKR can tolerate a certain level of structural irregularities (e.g., mismatches, bulges) in dsRNA (79) and can be activated by cellular dsRNAs under various physiological conditions. For example, in the absence of ADAR1, cellular dsRNAs formed by unmodified IR-Alu were proposed to activate PKR (48). Similarly, breakdown of the nuclear membrane during mitosis and consequent exposure of an excess amount of nuclear IR-Alus were also proposed to activate PKR (82).…”

T time for ADAR : ADAR 1 is required for T cell self‐tolerance

“…For example, although patients display a significant ISG signature, the molecular trigger that initiates the type I IFN response is not known. The study by Nakahama and co‐workers now joins other studies suggesting that self‐nucleic acids may trigger autoimmune diseases . Identifying the immunostimulatory self‐RNAs (presumably SINE RNAs or other endogenous RNA species) and investigating the molecular mechanisms by which ADAR1 prevents dsRNAs from activating PRRs could reveal insights into the underlying causes of various autoimmune diseases and clues on how to develop effective therapeutics.…”

Discrimination Between Self and Non-Self-Nucleic Acids by the Innate Immune System

“…However, A-to-I editing also alters the RNA secondary structure, which may lead to recognition by innate immune receptors (Liddicoat et al, 2015;Pestal et al, 2015). Recent data have shown that ADAR1 predominantly edits Alu elements in RNA polymerase II (pol II)-transcribed mRNAs, but not those transcribed by pol III in human cells (Chung et al, 2018), and A-to-I conversion in Alus suppresses MDA5 activation in vitro (Ahmad et al, 2018).…”