Detection of intracellular RNA or DNA triggers unique sensors to activate the antiviral response: foreign RNA activates the RIG-I-like receptor (RLR)-MAVS pathway, and foreign DNA activates the cGAS-STING pathway. These two antiviral pathways converge on a common set of signaling proteins to activate the type I interferon (IFN) response. However, despite this shared IFN response, the outcomes of RNA and DNA sensing are distinct at both transcriptional and cell biological levels. The unique components of each pathway that are responsible for these distinctions remain largely unknown. We have identified a heat shock protein called HSPA8/HSC70 that is inducibly phosphorylated on a specific serine residue after detection of intracellular DNA, but not after detection of RNA. This is the first signal-dependent, inducible phosphorylation event on HSPA8 identified to date. Interestingly, we have found that DNA-activated phosphorylation of HSPA8 occurs in cells derived from numerous primate and rodent species, but not in mouse cells, strongly suggesting that mice lack this novel innate immune response. HSPA8 plays pleiotropic and essential roles as a protein chaperone and as a regulator of membrane dynamics and autophagy, but its role in the antiviral response is unknown. In this grant, we will define the mechanism and specificity of HSPA8 phosphorylation, we will determine how this phosphorylation impacts the DNA-activated antiviral response, and we will explore the underlying reason for the absence of this response in mouse cells. This project will provide new insights into the DNA-activated antiviral response, it will reveal facets of antiviral immunity that cannot be modeled in mice, and it will create a framework for understanding how heat shock proteins participate in a specific innate immune pathway.

Public Health Relevance

Detection of intracellular DNA triggers an antiviral response that is essential for host defense against infection with DNA viruses and retroviruses. We have identified a unique heat shock protein that is inducibly phosphorylated on a specific serine residue in response to detection of intracellular DNA. We will determine the role that this heat shock protein plays in the DNA-activated antiviral response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI130940-01A1
Application #
9527588
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Liu, Qian
Project Start
2018-02-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195