Virology

Interferon

Immune system

RNA silencing

Biochemistry

Stress granule

Protein kinase R

RIG-I

Biology

Gene

Mitogen-activated protein kinase kinase

Cell biology

RNA interference

Signal transduction

Messenger RNA

Translation (biology)

MDA5

Innate immune system

Protein kinase C

Immunology

Journal of Biological Chemistry

A model by which ADAR1 p150 may suppress innate immune interferon responses triggered by cellular (self) RNA, but yet permits activation of the responses by viral (nonself) pathogen RNA, is summarized in Fig. 3. The findings described herein are consistent with the notion that A-to-I editing activity by ADAR1 in uninfected IFN-treated cells is capable of reducing the effective steady-state concentration of endogenous cellular (self) dsRNA structures to levels below the threshold concentration ordinarily required to trigger activation of the cellular dsRNA sensors (MDA5, PKR, and OAS). By contrast, in the absence of ADAR1 p150, the functional concentration of endogenous cytoplasmic self dsRNA increases to a level above the threshold necessary to trigger activation of MDA5, PKR, and OAS. Likewise, pathogen infection produces substantially elevated levels of dsRNA, well above the threshold both in the presence and absence of ADAR1. This then triggers activation of the MDA5, PKR, and OAS sensors, with the efficiency dependent upon the robustness of pathogen dsRNA production, as illustrated by the differences observed between WT (low dsRNA production) and C mutant (high dsRNA production) measles virus. Thus, ADAR1 regulates sensing of cellular (self) dsRNA structures, minimizing autotriggering of innate immune responses under conditions of low concentrations of dsRNA, yet permitting sensor activation by high concentrations of viral (nonself) dsRNAs produced in infected cells (73George C.X. Ramaswami G. Li J.B. Samuel C.E. Editing of cellular self-RNAs by adenosine deaminse ADAR1 suppresses innate immune stress responses.J. Biol. Chem. 2016; 291 (26817845): 6158-616810.1074/jbc.M115.709014Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 90Toth A.M. Li Z. Cattaneo R. Samuel C.E. RNA-specific adenosine deaminase ADAR1 suppresses measles virus-induced apoptosis and activation of protein kinase PKR.J. Biol. Chem. 2009; 284 (19710021): 29350-2935610.1074/jbc.M109.045146Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 127Chung H. Calis J.J.A. Wu X. Sun T. Yu Y. Sarbanes S.L. Dao Thi V.L. Shilvock A.R. Hoffmann H.H. Rosenberg B.R. Rice C.M. Human ADAR1 prevents endogenous RNA from triggering translational shutdown.Cell. 2018; 172 (29395325): 811-824.e1410.1016/j.cell.2017.12.038Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar).

Adenosine deaminase acting on RNA (ADAR1), a suppressor of double-stranded RNA–triggered innate immune responses