TY - JOUR
T1 - STING activation by translocation from the ER is associated with infection and autoinflammatory disease
AU - Dobbs, Nicole
AU - Burnaevskiy, Nikolay
AU - Chen, Didi
AU - Gonugunta, Vijay K.
AU - Alto, Neal M.
AU - Yan, Nan
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/8/12
Y1 - 2015/8/12
N2 - STING is an ER-associated membrane protein that is critical for innate immune sensing of pathogens. STING-mediated activation of the IFN-I pathway through the TBK1/IRF3 signaling axis involves both cyclic-dinucleotide binding and its translocation from the ER to vesicles. However, how these events are coordinated, and the exact mechanism of STING activation, remain poorly understood. Here, we found that the Shigella effector protein IpaJ potently inhibits STING signaling by blocking its translocation from the ER to ERGIC, even in the context of dinucleotide binding. Reconstitution using purified components revealed STING translocation as the rate-limiting event in maximal signal transduction. Furthermore, STING mutations associated with autoimmunity in humans were found to cause constitutive ER exit and to activate STING independent of cGAMP binding. Together, these data provide compelling evidence for an ER retention and ERGIC/Golgi-trafficking mechanism of STING regulation that is subverted by bacterial pathogens and is deregulated in human genetic disease.
AB - STING is an ER-associated membrane protein that is critical for innate immune sensing of pathogens. STING-mediated activation of the IFN-I pathway through the TBK1/IRF3 signaling axis involves both cyclic-dinucleotide binding and its translocation from the ER to vesicles. However, how these events are coordinated, and the exact mechanism of STING activation, remain poorly understood. Here, we found that the Shigella effector protein IpaJ potently inhibits STING signaling by blocking its translocation from the ER to ERGIC, even in the context of dinucleotide binding. Reconstitution using purified components revealed STING translocation as the rate-limiting event in maximal signal transduction. Furthermore, STING mutations associated with autoimmunity in humans were found to cause constitutive ER exit and to activate STING independent of cGAMP binding. Together, these data provide compelling evidence for an ER retention and ERGIC/Golgi-trafficking mechanism of STING regulation that is subverted by bacterial pathogens and is deregulated in human genetic disease.
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U2 - 10.1016/j.chom.2015.07.001
DO - 10.1016/j.chom.2015.07.001
M3 - Article
C2 - 26235147
AN - SCOPUS:84959353023
SN - 1931-3128
VL - 18
SP - 157
EP - 168
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 2
ER -