Projektdetails
Abstract
Equally important to appropriate induction of immune signaling are the molecular mechanisms preventing
accidental, and excessive/prolonged immune activation. This is achieved by base-line inhibitors, and negative
feed-back inhibitors induced during the anti-microbial response. Disruptions in these homeostatic mechanisms
can result in unwanted immune activation and hyper-inflammatory diseases. However, our knowledge on factors
that dampen these responses remains limited.
In a screen for negative immune regulators, we recently identified the virtually uncharacterized putative ubiquitin
E3 ligase TRIM52 as an inhibitor of the antiviral IFN-I response. Evolutionary analysis has indicated that the
Trim52 gene has been under positive selection pressure in humans, indeed suggestive of an immune-related
function. Domain prediction analysis has indicated that TRIM52 harbors a unique, exceptionally long RING
domain loop with unknown function.
Our follow-up experiments have shown that ablation of Trim52 results in increased levels of IFN-induced genes, in
line with a function as a baseline IFN-signaling inhibitor. Additional data indicate that TRIM52 is rapidly turned
over by the proteasome, yet transcriptionally induced during prolonged cell stress as seen during virus infections.
Based on these data, we hypothesize that TRIM52 is a baseline inhibitor of the IFN-I antiviral response.
Here, we will set out to investigate the contribution of TRIM52 to correct spatio-temporal repression of IFN-I
signaling, and consequently the anti-viral response. In this context, I propose the following two specific aims:
Aim1) Determine the importance of TRIM52 for the anti-viral response and its regulation during infection., and
Aim2) Determine the molecular mechanism by which TRIM52 represses IFN-I-dependent cell signaling.
For this project I request funding for two PhD students for three years: one for each of the aims. The success of
each aim is not dependent on the success of the other, yet both have great potential for synergy. For the
proposed project we will use viral infection models in cell lines and primary human broncho-epithelial cells. Stateof-
the-art genetic manipulations using lentiviral vectors for the delivery of genome engineering tools, ubiquitination
assays, as well as proteomics approaches will be used to achieve the set aims.
Together, the results from both aims will help us to understand in the long term how different molecules work
together at the cellular level to assure correct balance and activation in the immune response, and the
contribution to immune-related disease when these immune-regulatory mechanisms are deregulated.
Academic abstract
2515 - Versteeg
Creation
accidental, and excessive/prolonged immune activation. This is achieved by base-line inhibitors, and negative
feed-back inhibitors induced during the anti-microbial response. Disruptions in these homeostatic mechanisms
can result in unwanted immune activation and hyper-inflammatory diseases. However, our knowledge on factors
that dampen these responses remains limited.
In a screen for negative immune regulators, we recently identified the virtually uncharacterized putative ubiquitin
E3 ligase TRIM52 as an inhibitor of the antiviral IFN-I response. Evolutionary analysis has indicated that the
Trim52 gene has been under positive selection pressure in humans, indeed suggestive of an immune-related
function. Domain prediction analysis has indicated that TRIM52 harbors a unique, exceptionally long RING
domain loop with unknown function.
Our follow-up experiments have shown that ablation of Trim52 results in increased levels of IFN-induced genes, in
line with a function as a baseline IFN-signaling inhibitor. Additional data indicate that TRIM52 is rapidly turned
over by the proteasome, yet transcriptionally induced during prolonged cell stress as seen during virus infections.
Based on these data, we hypothesize that TRIM52 is a baseline inhibitor of the IFN-I antiviral response.
Here, we will set out to investigate the contribution of TRIM52 to correct spatio-temporal repression of IFN-I
signaling, and consequently the anti-viral response. In this context, I propose the following two specific aims:
Aim1) Determine the importance of TRIM52 for the anti-viral response and its regulation during infection., and
Aim2) Determine the molecular mechanism by which TRIM52 represses IFN-I-dependent cell signaling.
For this project I request funding for two PhD students for three years: one for each of the aims. The success of
each aim is not dependent on the success of the other, yet both have great potential for synergy. For the
proposed project we will use viral infection models in cell lines and primary human broncho-epithelial cells. Stateof-
the-art genetic manipulations using lentiviral vectors for the delivery of genome engineering tools, ubiquitination
assays, as well as proteomics approaches will be used to achieve the set aims.
Together, the results from both aims will help us to understand in the long term how different molecules work
together at the cellular level to assure correct balance and activation in the immune response, and the
contribution to immune-related disease when these immune-regulatory mechanisms are deregulated.
Academic abstract
2515 - Versteeg
Creation
Status | Abgeschlossen |
---|---|
Tatsächlicher Beginn/ -es Ende | 1/11/17 → 30/04/22 |
Schlagwörter
- ubiquitin
- tripartite motif protein
- TRIM
- interferon
- virus infection