RESUMO
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.
Assuntos
Adenosina Desaminase/metabolismo , Elementos Alu , Doenças Autoimunes do Sistema Nervoso/metabolismo , Malformações do Sistema Nervoso/metabolismo , Células-Tronco Neurais/metabolismo , Biossíntese de Proteínas , RNA de Cadeia Dupla/metabolismo , Proteínas de Ligação a RNA/metabolismo , Adenosina Desaminase/genética , Adenosina Desaminase/imunologia , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Morte Celular/genética , Morte Celular/imunologia , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Helicase IFIH1 Induzida por Interferon/genética , Helicase IFIH1 Induzida por Interferon/imunologia , Helicase IFIH1 Induzida por Interferon/metabolismo , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/imunologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/imunologia , Células-Tronco Neurais/patologia , RNA Polimerase II/genética , RNA Polimerase II/imunologia , RNA Polimerase II/metabolismo , RNA de Cadeia Dupla/genética , RNA de Cadeia Dupla/imunologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , eIF-2 Quinase/genética , eIF-2 Quinase/imunologia , eIF-2 Quinase/metabolismoRESUMO
The dorsal mesentery (DM) is the major conduit for blood and lymphatic vessels in the gut. The mechanisms underlying their morphogenesis are challenging to study and remain unknown. Here we show that arteriogenesis in the DM begins during gut rotation and proceeds strictly on the left side, dependent on the Pitx2 target gene Cxcl12. Although competent Cxcr4-positive angioblasts are present on the right, they fail to form vessels and progressively emigrate. Surprisingly, gut lymphatics also initiate in the left DM and arise only after-and dependent on-arteriogenesis, implicating arteries as drivers of gut lymphangiogenesis. Our data begin to unravel the origin of two distinct vascular systems and demonstrate how early left-right molecular asymmetries are translated into organ-specific vascular patterns. We propose a dual origin of gut lymphangiogenesis in which prior arterial growth is required to initiate local lymphatics that only subsequently connect to the vascular system.