Toll-like receptor 7 (TLR7) triggers antiviral immune responses by recognizing viral single-stranded RNA in endosomes. Although this mechanism underscores the ability of TLR7 to distinguish between self and not self RNA, the biosynthetic pathway of TLR7 remains unclear. Here, we show for the first time that human TLR7 is proteolytically processed and that the C-terminal fragment selectively accumulates in endocytic compartments, where it is functionally active. Human TLR7 processing depends on the action of furin-like proprotein convertases and occurs at neutral pH. Knockdown of Furin and mutation of a furin-like recognition site within TLR7 inhibits processing of the receptor. Furthermore pro-inflammatory stimuli such as PMA and IFN-γ enhance processing of and signalling through TLR7, consistent with an observed upregulation of Furin. This mechanism might serve as a positive feedback loop generating active TLR7 after infection. As self-RNA can under certain conditions activate TLR7 and trigger autoimmunity, our results identify furin-like proprotein convertases as a possible target to attenuate TLR7-dependent autoimmunity and other immune pathologies.
- Copyright © 2013 by The American Association of Immunologists, Inc.