de Oliveira Mann, Carina, Orzalli, Megan, King, David , Kagan, Jonathan, Lee, Amy and Kranzusch, Philip (2019) Modular architecture of the STING C-terminal tail allows interferon and NF-κB signaling adaptation. Cell reports. ISSN 2211-1247

Abstract

Stimulator of Interferon Genes (STING) is a key regulator of type I interferon and pro3
inflammatory responses during infection, cellular stress, and cancer. Here we reveal a
mechanism for how STING balances activation of IRF3- and NF-κB-dependent transcription,
and discover that acquisition of discrete signaling modules in the vertebrate STING C-terminal
tail (CTT) shapes downstream immunity. As a defining example, we identify a motif appended to
the CTT of zebrafish STING that inverts the typical vertebrate signaling response and results in
dramatic NF-κB activation and weak IRF3-interferon signaling. We determine a co-crystal
structure that explains how this CTT sequence recruits TRAF6 as a new binding partner, and
demonstrate that the minimal motif is sufficient to reprogram human STING and immune
activation in macrophage cells. Together, our results define the STING CTT as a linear signaling
hub that can acquire modular motifs to readily adapt downstream immunity.

Item Type:	Article
Date Deposited:	14 May 2019 00:45
Last Modified:	14 May 2019 00:45
URI:	https://oak.novartis.com/id/eprint/38388