Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown.
Cell
; 172(4): 811-824.e14, 2018 02 08.
Article
en En
| MEDLINE
| ID: mdl-29395325
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Biosíntesis de Proteínas
/
ARN Bicatenario
/
Adenosina Desaminasa
/
Proteínas de Unión al ARN
/
Elementos Alu
/
Enfermedades Autoinmunes del Sistema Nervioso
/
Células-Madre Neurales
/
Malformaciones del Sistema Nervioso
Idioma:
En
Revista:
Cell
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos