Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 19, Pages 8047-8052Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0700664104
Keywords
cell cycle; p27
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TRIF is an adaptor protein associated with the signaling by Toll-like receptor (TLR)3 and TLR4 for the induction of type I IFNs. Here, we demonstrate a mechanism by which TLR signaling controls cell proliferation and survival. We show that TLR3 and TLR4 can induce cell cycle entry via TRIF, which targets the cell cycle inhibitor p27(kip1) for relocalization, phosphorylation by cyclin/cdk complexes, and proteasome degradation. These events are antagonized by type I IFN induced by the TRIF pathway. Furthermore, in human dendritic cells treated with TLR3, TLR4, or TLR5 ligands, we demonstrate that IFN signaling modulates p27kipl degradation and apoptosis, identifying an immunoregulatory switching function of type I IFNs. These findings reveal a previously uncharacterized function of TLR signaling in cell proliferation and survival.
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