Modular Architecture of the STING C-Terminal Tail Allows Interferon and NF-κB Signaling Adaptation

de Oliveira Mann, Carina C.; Orzalli, Megan H.; King, David S.; Kagan, Jonathan C.; Lee, Amy S. Y.; Kranzusch, Philip J.

doi:10.1016/j.celrep.2019.03.098

Title: Modular Architecture of the STING C-Terminal Tail Allows Interferon and NF-κB Signaling Adaptation

Journal Article · Tue Apr 23 00:00:00 EDT 2019 · Cell Reports

DOI:https://doi.org/10.1016/j.celrep.2019.03.098· OSTI ID:1569888

de Oliveira Mann, Carina C. ^[1]; Orzalli, Megan H. ^[2]; King, David S. ^[3]; Kagan, Jonathan C. ^[2]; Lee, Amy S. Y. ^[4]; Kranzusch, Philip J. ^[1]

Harvard Medical School, Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States)
Boston Children's Hospital and Harvard Medical School, Boston, MA (United States)
Univ. of California, Berkeley, CA (United States). HHMI Mass Spectrometry Lab.
Brandeis Univ., Waltham, MA (United States)

Stimulator of interferon genes (STING) is a key regulator of type I interferon and pro-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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH); Cancer Research Institute

Grant/Contract Number:: AC02-06CH11357; AI133524; AI093589; AI116550; P30DK34854; T32AI007512; K99AI30258; P41 GM103403

OSTI ID:: 1569888

Journal Information:: Cell Reports, Vol. 27, Issue 4; ISSN 2211-1247

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 78 works

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59 BASIC BIOLOGICAL SCIENCES
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NF-kB
innate immunity

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