MDR | Structural and functional characterization of MAVS-DDX3-vRNA complex

Summary
The mitochondrial antiviral signalling (MAVS) adaptor protein is a central signalling hub for host cells to mount an antiviral response following RNA virus infections, which is initiated by the cytosolic receptors that trigger the type-I interferon (INFs) path through the MAVS. Recently, it has been shown that the RNA helicase DDX3 is a novel atypical member of the viral cytosolic receptor pool and it is required to activate the MAVS during the antiviral response. In fact, DDX3 is crucial in the translation initiation of the HIV-1 RNA and it is identified as viral RNA sensor able to induce the antiviral immunity in dendritic cells (DCs). DDX3 binds to viral RNAs lacking the poly(A) tails, also known as abortive transcripts, and then associates with the MAVS to trigger the production of type I IFN.
Currently, it is unknown how the complex partners MAVS-DDX3-vRNA (MDR) interact for assembly and what is the MDR mechanism of action at molecular level.
The proposed research will be focused on the structural and functional characterization of the MDR complex by biophysical and cellular biology techniques. Notably, silencing DDX3 or MAVS expression suppress DC activation in response to HIV-1 infection, an event that in physiological condition is at the front line of host defence against the HIV-1. Therefore, the central role in triggering antiviral immune response makes MDR a strategic pharmacological target. However, addressing this task requires the MDR structure elucidation in order to exploit its molecular features to create a new generation of adjuvants in anti-retroviral therapy.
This research provides an understanding of how cellular protein sensors interact with retroviral RNA to trigger the native immune response and induce expression of antiviral proteins.
Unfold all
/
Fold all
More information & hyperlinks
Web resources: https://cordis.europa.eu/project/id/844115
Start date: 01-09-2019
End date: 31-08-2022
Total budget - Public funding: 187 572,48 Euro - 187 572,00 Euro
Cordis data

Original description

The mitochondrial antiviral signalling (MAVS) adaptor protein is a central signalling hub for host cells to mount an antiviral response following RNA virus infections, which is initiated by the cytosolic receptors that trigger the type-I interferon (INFs) path through the MAVS. Recently, it has been shown that the RNA helicase DDX3 is a novel atypical member of the viral cytosolic receptor pool and it is required to activate the MAVS during the antiviral response. In fact, DDX3 is crucial in the translation initiation of the HIV-1 RNA and it is identified as viral RNA sensor able to induce the antiviral immunity in dendritic cells (DCs). DDX3 binds to viral RNAs lacking the poly(A) tails, also known as abortive transcripts, and then associates with the MAVS to trigger the production of type I IFN.
Currently, it is unknown how the complex partners MAVS-DDX3-vRNA (MDR) interact for assembly and what is the MDR mechanism of action at molecular level.
The proposed research will be focused on the structural and functional characterization of the MDR complex by biophysical and cellular biology techniques. Notably, silencing DDX3 or MAVS expression suppress DC activation in response to HIV-1 infection, an event that in physiological condition is at the front line of host defence against the HIV-1. Therefore, the central role in triggering antiviral immune response makes MDR a strategic pharmacological target. However, addressing this task requires the MDR structure elucidation in order to exploit its molecular features to create a new generation of adjuvants in anti-retroviral therapy.
This research provides an understanding of how cellular protein sensors interact with retroviral RNA to trigger the native immune response and induce expression of antiviral proteins.

Status

TERMINATED

Call topic

MSCA-IF-2018

Update Date

28-04-2024
Images
No images available.
Geographical location(s)
Structured mapping
Unfold all
/
Fold all
Horizon 2020
H2020-EU.1. EXCELLENT SCIENCE
H2020-EU.1.3. EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions (MSCA)
H2020-EU.1.3.2. Nurturing excellence by means of cross-border and cross-sector mobility
H2020-MSCA-IF-2018
MSCA-IF-2018