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PELI2 is a negative regulator of STING signaling that is dynamically repressed during viral infection.
Ritchie, Christopher; Li, Lingyin.
Afiliación
  • Ritchie C; Department of Biochemistry, Stanford University, Stanford, CA 94305, USA; Sarafan ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Arc Institute, Palo Alto, CA 94304, USA. Electronic address: chrisr@arcinstitute.org.
  • Li L; Department of Biochemistry, Stanford University, Stanford, CA 94305, USA; Sarafan ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Arc Institute, Palo Alto, CA 94304, USA. Electronic address: lingyin@arcinstitute.org.
Mol Cell ; 84(13): 2423-2435.e5, 2024 Jul 11.
Article en En | MEDLINE | ID: mdl-38917796
ABSTRACT
The innate immune cGAS-STING pathway is activated by cytosolic double-stranded DNA (dsDNA), a ubiquitous danger signal, to produce interferon, a potent anti-viral and anti-cancer cytokine. However, STING activation must be tightly controlled because aberrant interferon production leads to debilitating interferonopathies. Here, we discover PELI2 as a crucial negative regulator of STING. Mechanistically, PELI2 inhibits the transcription factor IRF3 by binding to phosphorylated Thr354 and Thr356 on the C-terminal tail of STING, leading to ubiquitination and inhibition of the kinase TBK1. PELI2 sets a threshold for STING activation that tolerates low levels of cytosolic dsDNA, such as that caused by silenced TREX1, RNASEH2B, BRCA1, or SETX. When this threshold is reached, such as during viral infection, STING-induced interferon production temporarily downregulates PELI2, creating a positive feedback loop allowing a robust immune response. Lupus patients have insufficient PELI2 levels and high basal interferon production, suggesting that PELI2 dysregulation may drive the onset of lupus and other interferonopathies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Proteínas Serina-Treonina Quinasas / Factor 3 Regulador del Interferón / Ubiquitinación / Proteínas de la Membrana Límite: Animals / Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Proteínas Serina-Treonina Quinasas / Factor 3 Regulador del Interferón / Ubiquitinación / Proteínas de la Membrana Límite: Animals / Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos