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TIPE2 controls innate immunity to RNA by targeting the phosphatidylinositol 3-kinase-Rac pathway.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2012 Sep 15; Vol. 189 (6), pp. 2768-73. Date of Electronic Publication: 2012 Aug 17. - Publication Year :
- 2012
-
Abstract
- RNA receptors such as TLR3 and retinoid acid-inducible gene I/melanoma differentiation-associated gene 5 play essential roles in innate immunity to RNA viruses. However, how innate immunity to RNAs is controlled at the molecular level is not well understood. We describe in this study a new regulatory pathway of anti-RNA immunity that is composed of PI3K, its target GTPase Rac, and the newly described immune regulator TNF-α-induced protein 8 like-2 (TIPE2, or TNFAIP8L2). Polyinosinic-polycytidylic acid [Poly (I:C)], a dsRNA receptor ligand, activates Rac via its guanine nucleotide exchange factor Tiam; this leads to the activation of cytokine genes and, paradoxically, downregulation of the Tipe2 gene. TIPE2 is a negative regulator of immunity; its deficiency leads to hyperactivation of the PI3K-Rac pathway as exemplified by enhanced AKT, Rac, P21-activated kinase, and IFN regulatory factor 3 activities. As a consequence, TIPE2 knockout myeloid cells are hyperreactive to Poly (I:C) stimulation, and TIPE2 knockout mice are hypersensitive to Poly (I:C)-induced lethality. These results indicate that TIPE2 controls innate immunity to RNA by targeting the PI3K-Rac pathway. Therefore, manipulating TIPE2 or Rac functions can be effective for controlling RNA viral infections.
- Subjects :
- Animals
Cells, Cultured
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins deficiency
Intracellular Signaling Peptides and Proteins genetics
L Cells
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphoinositide-3 Kinase Inhibitors
Poly I-C antagonists & inhibitors
Poly I-C pharmacology
Signal Transduction genetics
rac GTP-Binding Proteins antagonists & inhibitors
rac GTP-Binding Proteins physiology
Immunity, Innate genetics
Intracellular Signaling Peptides and Proteins physiology
Phosphatidylinositol 3-Kinase physiology
Signal Transduction immunology
rac GTP-Binding Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 189
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 22904303
- Full Text :
- https://doi.org/10.4049/jimmunol.1103477