| First Author | Jones PH | Year | 2013 |
| Journal | Cell Signal | Volume | 25 |
| Issue | 12 | Pages | 2752-61 |
| PubMed ID | 24036213 | Mgi Jnum | J:318192 |
| Mgi Id | MGI:6858687 | Doi | 10.1016/j.cellsig.2013.08.042 |
| Citation | Jones PH, et al. (2013) Phosphatidylinositol 3-kinase is involved in Toll-like receptor 4-mediated BST-2/tetherin regulation. Cell Signal 25(12):2752-61 |
| abstractText | BST-2 is a virus restriction factor whose expression is principally induced by IFNalpha through the type I IFN receptor. However, expression of BST-2 is modulated by mitogens, notably the TLR4 agonist - LPS, via mechanisms that are poorly understood. In this study, the role of TLR4 pathway on BST-2 expression was examined. We demonstrate that the TLR4/PI3K signaling pathway regulates both constitutive and LPS-induced BST-2 expression. LPS stimulation induces BST-2 expression in a manner dependent on TLR4/TRIF/IRF3 pathway. Genetic deletion or pharmacological inhibition of signaling through TLR4, as well as, the deletion of the TRIF and IRF3 genes blunts BST-2 induction by LPS. However, MYD88-/- cells have enhanced BST-2 levels and respond to LPS-mediated induction of BST-2. High level of BST-2 in MYD88 null cells is dependent on IFNbeta since antibody-mediated neutralization of IFNbeta synthesis results in reduced BST-2 levels in these cells. Similar to the effect of MYD88, inhibition of PI3K activity elevates basal BST-2 level and augments LPS-induced BST-2 expression. Importantly, BST-2 regulation via TLR4 and PI3K is transcriptionally controlled. We discovered that actinomycin D-mediated blocking of gene transcription and inhibition of protein synthesis with cycloheximide result in impairment of BST-2 mRNA expression. Taken together, our results demonstrate that activation of TLR4 results in TRIF/IRF3-mediated positive regulation of BST-2 or MYD88/PI3K-directed negative regulation of BST-2. Thus, our findings enlist BST-2 as one of the genes regulated by PI3K downstream of TLR4 and identify the TLR4/PI3K signaling as a novel pathway that controls BST-2 expression. |
