Title:Novel mechanisms of regulating Toll-like receptor signalling-implications for anti-viral immunity

Presenter: Sinead Miggin, PhD

University: Alpert Medical School and Brown University, USA

Time: 15:00-16:00, April 9, 2013

Venue: Room A203, Institute of Microbiology, Chinese Academy of Sciences

Abstract: Toll-like receptors (TLRs) are a group of pattern-recognition receptors that play a crucial role in the induction of the innate immune response against bacterial and viral infections. TLR3 has emerged as a key sensor of viral double-stranded RNA. Thus, a clearer understanding of the biological processes that modulate TLR3 signaling through the adaptor molecule, TRIF, is essential. Limited studies have applied proteomics towards understanding the dynamics of TLR signaling. Herein, a proteomics approach identified 14-3-3ε, 14-3-3σ and A Disintegrin and Metalloprotease (ADAM)15 as new members of the TLR signaling complex.

Towards the functional characterization of 14-3-3ε and 14-3-3σ in TLR signaling, we have shown that both of these proteins modulate TLR2, TLR3, TLR4, TLR7/8 and TLR9 signaling. 14-3-3ε and 14-3-3σ also bind to the TLR adaptors and to both TRAF3 and TRAF6. We also show that ADAM15 acts as a negative regulator of TRIF mediated NF-κB and IFNβ reporter gene activity. Also, suppression of ADAM15 expression enhances poly(I:C) and LPS-mediated proinflammatory cytokine production via TRIF. In addition, suppression of ADAM15 expression enhanced RV16 and VSV-mediated proinflammatory cytokine production.

Our research conclusively shows that 14-3-3ε, 14-3-3σ and ADAM15 play major regulatory roles in balancing the host inflammatory response to viral and bacterial infections through modulation of the TLR signaling pathway. Thus, manipulation of these proteins may represent novel therapeutic targets for inflammatory conditions and infections.