Our data indicates that STING (Stimulator of interferon genes) controls a key cytosolic DNA-sensing pathway and is responsible for DNaseII-deficient lethality and chronic polyarthritis (CP) as well as TREX1-mediated SLE-like disease in mice. For example, DNaseII mice die during embryonic development due to undigested DNA derived from apoptotic cells activating DNA sensors that trigger the production of type I IFN and pro- inflammatory cytokines. DNaseII-/- mice are born normally in the absence of STING, however, without any signs of inflammation-aggravated disease. Further, TREX1-/- mice which have a median lifespan of 10 weeks due to the development of inflammatory myocarditis remain viable when crossed onto a STING-/- background, and do not exhibit such disease. Mutations inTREX1 have been shown to be involved in Aicardi-Goutieres syndrome (AGS) in humans, typified by high levels of circulating type I IFN and early death. Despite this significant progres, the mechanisms that control STING function and the cytosolic DNA signaling pathway remain to be fully clarified. We thus propose two aims. The first is to further understand the mechanisms controlling STING function, such as by phosphorylation and the triggering of cytokine production responsible for inflammatory disease.
The second aim i s to study the mechanisms by which Trex1 may regulate STING. These objectives will shed considerable insight into mechanisms of innate immunity as well as into the causes of inflammatory disease.

Public Health Relevance

More than 20% of the population of the United States (US) has been reported to suffer from inflammatory disorders such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Both of these syndromes have no known etiology and the mechanisms of disease initiation and progression remain unclear. We have found a potential cause of these diseases that could be targeted by therapeutics to prevent inflammatory-related disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079336-09
Application #
9380288
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Jiang, Chao
Project Start
2008-08-01
Project End
2019-10-31
Budget Start
2017-11-01
Budget End
2018-10-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Ni, Guoxin; Konno, Hiroyasu; Barber, Glen N (2017) Ubiquitination of STING at lysine 224 controls IRF3 activation. Sci Immunol 2:
Xia, Tianli; Konno, Hiroyasu; Ahn, Jeonghyun et al. (2016) Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis. Cell Rep 14:282-97
Mukai, Kojiro; Konno, Hiroyasu; Akiba, Tatsuya et al. (2016) Activation of STING requires palmitoylation at the Golgi. Nat Commun 7:11932
Hyun, Jinhee; Ramos, Juan Carlos; Toomey, Ngoc et al. (2015) Oncogenic human T-cell lymphotropic virus type 1 tax suppression of primary innate immune signaling pathways. J Virol 89:4880-93
Barber, Glen N (2015) STING: infection, inflammation and cancer. Nat Rev Immunol 15:760-70
Ahn, J; Konno, H; Barber, G N (2015) Diverse roles of STING-dependent signaling on the development of cancer. Oncogene 34:5302-8
Ma, Zhe; Jacobs, Sarah R; West, John A et al. (2015) Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses. Proc Natl Acad Sci U S A 112:E4306-15
Woo, Seng-Ryong; Fuertes, Mercedes B; Corrales, Leticia et al. (2014) STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41:830-42
Yarbrough, Melanie L; Zhang, Ke; Sakthivel, Ramanavelan et al. (2014) Primate-specific miR-576-3p sets host defense signalling threshold. Nat Commun 5:4963
Abe, Takayuki; Barber, Glen N (2014) Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-?B activation through TBK1. J Virol 88:5328-41

Showing the most recent 10 out of 21 publications