Innate immune response to infectious agents or local cell damage constitutes a major mammalian defense mechanism. Inflammatory cytokines and interferons are produced, mainly by myeloid cells, in response to bacterial or viral infection and they limit the microbial infection by either acting directly on the infected cells or activating immune cells of the adaptive immune system. There are multiple cytoplasmic pattern recognition receptors for sensing cytoplasmic DNA produced by either infecting microbes or damaged nuclei or mitochondria. All of these receptors use STING as the common signaling adaptor protein. This proposal is for investigating two novel features of STING signaling that were revealed by our preliminary experiments. Although TRIF is a known adaptor protein for TLR3 and TLR4 signaling, we discovered that it promotes STING signaling as well.
Our aim i s to determine how TRIF functions in the STING signaling pathway and how it affects resistance against HSV-1, a virus that triggers the STING signaling pathway. We have also observed that, like several TLRs, STING requires tyrosine phosphorylation to trigger its signaling activity. Moreover, the protein tyrosine kinase activity of the epidermal growth factor receptor (EGFR) is required for STING Tyr phosphorylation and its ability to induce cytokine genes.
Our second aim i s to investigate the mechanism of EGFR-mediated STING Tyr phosphorylation and its role in downstream signaling. Our proposed studies will illuminate new features of STING signaling, which is essential for eliciting innate immune response to cytoplasmic DNA.

Public Health Relevance

Microbes that infect and multiply in mammalian cells, often trigger cellular innate immune responses to protect the host cells. STING is the cellular adaptor protein which is required for triggering responses to all cytoplasmic DNA. This proposal is focused on investigating two new features of STING signaling. We will determine how TRIF, an adaptor protein for TLRs, promotes STING signaling. We will also examine how the protein tyrosine kinase activity of the epidermal growth factor receptor promotes STING phosphorylation and signaling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI123783-01
Application #
9086042
Study Section
Special Emphasis Panel (ZRG1-IMM-D (90))
Program Officer
Lapham, Cheryl K
Project Start
2016-02-10
Project End
2018-01-31
Budget Start
2016-02-10
Budget End
2017-01-31
Support Year
1
Fiscal Year
2016
Total Cost
$237,750
Indirect Cost
$87,750
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Wang, Xin; Majumdar, Tanmay; Kessler, Patricia et al. (2016) STING Requires the Adaptor TRIF to Trigger Innate Immune Responses to Microbial Infection. Cell Host Microbe 20:329-41