RESUMEN
In this issue, He et al. (2015) show how herpes virus usurps a cellular metabolic enzyme to induce RIG-I deamidation and RNA-independent activation, likely to better prevent further innate immune responses.
Asunto(s)
Ligasas de Carbono-Nitrógeno con Glutamina como Donante de Amida-N/inmunología , ARN Helicasas DEAD-box/inmunología , Gammaherpesvirinae/inmunología , Evasión Inmune/genética , ARN Viral/inmunología , Proteínas Virales/inmunología , Animales , Proteína 58 DEAD Box , Humanos , Receptores InmunológicosRESUMEN
RIG-I is a pattern recognition receptor that senses viral RNA and is crucial for host innate immune defense. Here, we describe a mechanism of RIG-I activation through amidotransferase-mediated deamidation. We show that viral homologs of phosphoribosylformylglycinamidine synthetase (PFAS), although lacking intrinsic enzyme activity, recruit cellular PFAS to deamidate and activate RIG-I. Accordingly, depletion and biochemical inhibition of PFAS impair RIG-I deamidation and concomitant activation. Purified PFAS and viral homolog thereof deamidate RIG-I in vitro. Ultimately, herpesvirus hijacks activated RIG-I to avoid antiviral cytokine production; loss of RIG-I or inhibition of RIG-I deamidation results in elevated cytokine production. Together, these findings demonstrate a surprising mechanism of RIG-I activation that is mediated by an enzyme.
Asunto(s)
Ligasas de Carbono-Nitrógeno con Glutamina como Donante de Amida-N/inmunología , ARN Helicasas DEAD-box/inmunología , Gammaherpesvirinae/inmunología , Evasión Inmune/genética , ARN Viral/inmunología , Proteínas Virales/inmunología , Amidas/metabolismo , Animales , Ligasas de Carbono-Nitrógeno con Glutamina como Donante de Amida-N/genética , Línea Celular , Citocinas/antagonistas & inhibidores , Citocinas/biosíntesis , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/antagonistas & inhibidores , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Activación Enzimática , Fibroblastos/enzimología , Fibroblastos/inmunología , Fibroblastos/virología , Gammaherpesvirinae/genética , Regulación de la Expresión Génica , Células HEK293 , Humanos , Inmunidad Innata , Ratones , Imitación Molecular , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , ARN Viral/genética , Receptores Inmunológicos , Transducción de Señal , Proteínas Virales/genéticaRESUMEN
Purines are critical for energy metabolism, cell signalling and cell reproduction. Nevertheless, little is known about the regulation of this essential biochemical pathway during mammalian development. In humans, the second, third and fifth steps of de novo purine biosynthesis are catalyzed by a trifunctional protein with glycinamide ribonucleotide synthetase (GARS), aminoimidazole ribonucleotide synthetase (AIRS) and glycinamide ribonucleotide formyltransferase (GART) enzymatic activities. The gene encoding this trifunctional protein is located on chromosome 21. The enzyme catalyzing the intervening fourth step of de novo purine biosynthesis, phosphoribosylformylglycineamide amidotransferase (FGARAT), is encoded by a separate gene on chromosome 17. To investigate the regulation of these proteins, we have generated monoclonal and/or polyclonal antibodies specific to each of these enzymatic domains. Using these antibodies on western blots of Chinese hamster ovary (CHO) cells transfected with the human GARS-AIRS-GART gene, we show that this gene encodes not only the trifunctional protein of 110 kDa, but also a monofunctional GARS protein of 50 kDa. This carboxy-truncated human GARS protein is produced by alternative splicing resulting in the use of a polyadenylation site in the intron between the terminal GARS and the first AIRS exons. The expression of both the GARS and GARS-AIRS-GART proteins are regulated during development of the human cerebellum, while the expression of FGARAT appears to be constitutive. All three proteins are expressed at high levels during normal prenatal cerebellum development while the GARS and GARS-AIRS-GART proteins become undetectable in this tissue shortly after birth. In contrast, the GARS and GARS-AIRS-GART proteins continue to be expressed during the postnatal development of the cerebellum in individuals with Down syndrome.
