Final Report Summary - IFNDNA (Innate immune recognition of intracellular DNA as 'stranger' and 'danger' signal)
This project aimed to investigate the innate immune response to intracellular DNA. DNA can be recognised as a "stranger" signal, for instance when DNA is detected in the cytosol during infection with viruses and other intracellular pathogens. Our own DNA can also be sensed as "danger" signal, for instance when DNA damage is detected in the nucleus.
The objectives of this research programme are:
1.) To test the involvement of DNA receptors in the recognition of DNA as 'stranger' and 'danger' signal in human cells
2.) To examine the interplay between different DNA receptor candidates
3.) To identify novel regulators of the DNA-induced signalling pathway
4.) To define the nature of the DNA ligand that is recognised by innate immune receptors
This project contributed to a work programme investigating the role of the cytosolic DNA receptor cGAS (cyclic GMP-AMP synthase) and the nuclear DNA binding protein IFI16 (interferon-gamma-inducible protein 16) in the detection of cytosolic pathogen DNA and nuclear DNA damage. We investigated the function of innate immune signalling cascades involved in DNA sensing in human cells, and particularly in keratinocytes. These cells at the surface of our skin are emerging as key sentinels for the initiation of local immune responses during infection and injury. During this project, we discovered that the DNA binding protein IFI16 co-operates with the DNA receptor cGAS in the detection of cytosolic DNA during infection, and that both proteins are required for the full activation of their adaptor protein STING (STimulator of INterferon Genes). We have also uncovered a novel innate immune signalling cascade that links the detection of DNA damage int he nucleus to the activation of STING at the edoplasmic reticulum. This signalling cascade is unusual, in that it does not involve DNA recognition by cGAS in the cytosol, but instead relies on IFI16 and nuclear DNA damage factors which promote a non-canonical mode of STING activation. The non-canonical activation of STING under these conditions involves its modification by K63-linked ubiquitin chains, and we have identified the ubiquitin ligase TRAF6 as a regulator of STING function after DNA damage.
Non-canonical STING activation results in an alternative transcription factor activation profile, and a different cytokline expression programme compared to conventional DNA sensing. We hypothesise that STING acts as an innate immune signalling hub which integrates different input signals, for instance after detection of different kinds of DNA damage or the recognition of nuclear or cytosolic DNA viruses.
The regulation of DNA sensing pathways and STING activation is crucial in a variety of conditions, e.g. during infection with DNA viruses and other intracellular pathogens, during autoimmunity and during the immune response to tumour cells during immunosurveillance. We believe that this project has contributed to the fundamental understanding of these innate immune signalling cascades, and thus might be of clinical relevance for the development of novel immnunomodulatory therapeutics and cancer immunotherapy agents in the future.
Contact:
Dr Leonie Unterholzner
Division of Biomedical and Life Sciences
Faculty of Health and Medicine
Lancaster University
l.unterholzner@lancaster.ac.uk
https://www.lancaster.ac.uk/health-and-medicine/about-us/people/leonie-unterholzner
The objectives of this research programme are:
1.) To test the involvement of DNA receptors in the recognition of DNA as 'stranger' and 'danger' signal in human cells
2.) To examine the interplay between different DNA receptor candidates
3.) To identify novel regulators of the DNA-induced signalling pathway
4.) To define the nature of the DNA ligand that is recognised by innate immune receptors
This project contributed to a work programme investigating the role of the cytosolic DNA receptor cGAS (cyclic GMP-AMP synthase) and the nuclear DNA binding protein IFI16 (interferon-gamma-inducible protein 16) in the detection of cytosolic pathogen DNA and nuclear DNA damage. We investigated the function of innate immune signalling cascades involved in DNA sensing in human cells, and particularly in keratinocytes. These cells at the surface of our skin are emerging as key sentinels for the initiation of local immune responses during infection and injury. During this project, we discovered that the DNA binding protein IFI16 co-operates with the DNA receptor cGAS in the detection of cytosolic DNA during infection, and that both proteins are required for the full activation of their adaptor protein STING (STimulator of INterferon Genes). We have also uncovered a novel innate immune signalling cascade that links the detection of DNA damage int he nucleus to the activation of STING at the edoplasmic reticulum. This signalling cascade is unusual, in that it does not involve DNA recognition by cGAS in the cytosol, but instead relies on IFI16 and nuclear DNA damage factors which promote a non-canonical mode of STING activation. The non-canonical activation of STING under these conditions involves its modification by K63-linked ubiquitin chains, and we have identified the ubiquitin ligase TRAF6 as a regulator of STING function after DNA damage.
Non-canonical STING activation results in an alternative transcription factor activation profile, and a different cytokline expression programme compared to conventional DNA sensing. We hypothesise that STING acts as an innate immune signalling hub which integrates different input signals, for instance after detection of different kinds of DNA damage or the recognition of nuclear or cytosolic DNA viruses.
The regulation of DNA sensing pathways and STING activation is crucial in a variety of conditions, e.g. during infection with DNA viruses and other intracellular pathogens, during autoimmunity and during the immune response to tumour cells during immunosurveillance. We believe that this project has contributed to the fundamental understanding of these innate immune signalling cascades, and thus might be of clinical relevance for the development of novel immnunomodulatory therapeutics and cancer immunotherapy agents in the future.
Contact:
Dr Leonie Unterholzner
Division of Biomedical and Life Sciences
Faculty of Health and Medicine
Lancaster University
l.unterholzner@lancaster.ac.uk
https://www.lancaster.ac.uk/health-and-medicine/about-us/people/leonie-unterholzner