RESUMEN
Activation of the stimulator of interferon genes (STING) pathway by microbial or self-DNA, as well as cyclic dinucleotides (CDNs), results in the induction of numerous genes that suppress pathogen replication and facilitate adaptive immunity. However, sustained gene transcription is rigidly prevented to avoid lethal STING-dependent proinflammatory disease by mechanisms that remain unknown. We demonstrate here that, after autophagy-dependent STING delivery of TANK-binding kinase 1 (TBK1) to endosomal/lysosomal compartments and activation of transcription factors interferon regulatory factor 3 (IRF3) and NF-κB, STING is subsequently phosphorylated by serine/threonine UNC-51-like kinase (ULK1/ATG1), and IRF3 function is suppressed. ULK1 activation occurred following disassociation from its repressor AMP activated protein kinase (AMPK) and was elicited by CDNs generated by the cGAMP synthase, cGAS. Thus, although CDNs may initially facilitate STING function, they subsequently trigger negative-feedback control of STING activity, thus preventing the persistent transcription of innate immune genes.
Asunto(s)
Inmunidad Innata , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Secuencia de Aminoácidos , Homólogo de la Proteína 1 Relacionada con la Autofagia , Humanos , Proteínas de la Membrana/química , Datos de Secuencia Molecular , Nucleótidos Cíclicos/metabolismo , Fosforilación , Alineación de SecuenciaRESUMEN
How the cell recognizes cytosolic DNA including DNA-based microbes to trigger host-defense-related gene activation remains to be fully resolved. Here, we demonstrate that STING (stimulator of interferon genes), an endoplasmic reticulum translocon-associated transmembrane protein, acts to detect cytoplasmic DNA species. STING homodimers were able to complex with self- (apoptotic, necrotic) or pathogen-related ssDNA and dsDNA and were indispensible for HSV-1-mediated transcriptional activation of a wide array of innate immune and proinflammatory genes in addition to type I IFN. Our data indicate that STING instigates cytoplasmic DNA-mediated cellular defense gene transcription and facilitates adoptive responses that are required for protection of the host. In contrast, chronic STING activation may manifest inflammatory responses and possibly autoimmune disease triggered by self-DNA.
Asunto(s)
Citoplasma/metabolismo , ADN de Cadena Simple/metabolismo , Proteínas de la Membrana/metabolismo , Animales , Apoptosis , Sitios de Unión , Citoplasma/inmunología , ADN de Cadena Simple/inmunología , Genes Reporteros , Células HEK293 , Herpesvirus Humano 1/inmunología , Humanos , Inmunidad Innata , Mediadores de Inflamación/metabolismo , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , Luciferasas de Luciérnaga/biosíntesis , Luciferasas de Luciérnaga/genética , Proteínas de la Membrana/genética , Ratones , Necrosis , Multimerización de Proteína , Interferencia de ARN , Telomerasa/genética , Telomerasa/metabolismo , Transcripción Genética , TransfecciónRESUMEN
Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by mechanisms that are not well understood. Here we demonstrate that mutagenic 7,12-dimethylbenz(a)anthracene (DMBA), cisplatin and etoposide induce nuclear DNA leakage into the cytosol that intrinsically activates stimulator of interferon genes (STING)-dependent cytokine production. Inflammatory cytokine levels are subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING(-/-) mice, or wild-type mice adoptively transferred with STING(-/-) bone marrow, are almost completely resistant to DMBA-induced skin carcinogenesis compared with their wild-type counterparts. Our data establish a role for STING in the control of cancer, shed significant insight into the causes of inflammation-driven carcinogenesis and may provide a basis for therapeutic strategies to help prevent malignant disease.
Asunto(s)
Proteínas de la Membrana/inmunología , Neoplasias Cutáneas/inmunología , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Animales , Carcinogénesis/genética , Carcinogénesis/inmunología , Carcinogénesis/patología , Citocinas/genética , Citocinas/inmunología , Exodesoxirribonucleasas/genética , Exodesoxirribonucleasas/inmunología , Femenino , Humanos , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Fosfoproteínas/genética , Fosfoproteínas/inmunología , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
An 81-year-old man was admitted to the hospital with a severe sore throat and a low grade fever. A chest radiograph showed bilateral diffuse reticulonodular shadows. By fluorescent stain for mycobacteria, his sputum smear showed acid-fast bacteria. The initial polymerase chain reaction (PCR) of his sputum revealed Mycobacterium intracellulare (M. intracellulare), but not Mycobacterium tuberculosis (M. tuberculosis). However, a repeat PCR was performed because M. tuberculosis could not be ruled out due to his clinical symptoms and chest imaging. The second PCR detected both M. intracellulare and M. tuberculosis. From the standpoint of infection control, this case illustrates the possibility that M. tuberculosis could be a threat if a second PCR is not done. While PCR is a useful exam for diagnosing M. tuberculosis, it can produce false negative results. Therefore, for diagnosing tuberculosis, particularly in a case such as the present case, a second PCR, which is not normally necessary, should be done.