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The functional interactome of PYHIN immune regulators reveals IFIX is a sensor of viral DNA.

Diner BA, Li T, Greco TM, Crow MS, Fuesler JA, Wang J, Cristea IM - Mol. Syst. Biol. (2015)

Bottom Line: We discover that IFIX detects viral DNA in both the nucleus and cytoplasm, binding foreign DNA via its HIN domain in a sequence-non-specific manner.Furthermore, IFIX contributes to the induction of interferon response.Our results highlight the value of integrative proteomics in deducing protein function and establish IFIX as an antiviral DNA sensor important for mounting immune responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ, USA.

No MeSH data available.


Related in: MedlinePlus

The interaction network of the PYHIN protein family345 SAINT-filtered PYHIN–prey protein interactions, common between N- and C-terminally tagged PYHIN isolations, were assessed using the STRING database and visualized in Cytoscape. GO terms were assigned to individual prey nodes and color-coded based on assigned molecular functions (key, bottom left). The number of PYHIN proteins found to interact with a particular prey is represented by the prey node shape (key, bottom right). Known complexes are annotated and network edges indicate interactions with either a PYHIN protein or other prey proteins. Edgeless nodes are arranged in clusters closest to the PYHIN protein(s) with which they interact.
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fig03: The interaction network of the PYHIN protein family345 SAINT-filtered PYHIN–prey protein interactions, common between N- and C-terminally tagged PYHIN isolations, were assessed using the STRING database and visualized in Cytoscape. GO terms were assigned to individual prey nodes and color-coded based on assigned molecular functions (key, bottom left). The number of PYHIN proteins found to interact with a particular prey is represented by the prey node shape (key, bottom right). Known complexes are annotated and network edges indicate interactions with either a PYHIN protein or other prey proteins. Edgeless nodes are arranged in clusters closest to the PYHIN protein(s) with which they interact.

Mentions: To integrate the putative PYHIN interactions within a network and assess functional complex enrichment, we next searched the SAINT-filtered interactions from all PYHIN isolations against the STRING database of known protein association networks (Szklarczyk et al, 2011). Given the scarcity of information regarding PYHIN interactions and to avoid variations from the tag location, we chose to construct the network by illustrating interactions present with both N- and C-terminally tagged PYHIN proteins. These reflected the majority (345 out of 355) of the detected interactions (Supplementary Tables S4, S5 and S6). Individual PYHIN interaction networks were merged via Cytoscape (Shannon et al, 2003), and gene ontology (GO) terms were assigned to all interactions (Fig3 and Supplementary File S1). The relative enrichment of the proteins isolated with each bait was estimated by calculating a normalized spectral abundance factor (NSAF) for each protein (Zybailov et al, 2007), which was then normalized to the estimated abundance of the protein within the human proteome (PAX values) (Weiss et al, 2010), as we previously reported (Tsai et al, 2012). This analysis highlighted the most enriched SAINT-filtered interactions within the isolation of each PYHIN protein (Supplementary Figs S5, S6, S7 and S8). Interestingly, several prominent functional protein complexes were evident in the PYHIN network (Fig3). Consistent with our hierarchical clustering data, complexes involved in ribosome biogenesis and RNA processing were enriched within IFI16 and MNDA shared networks, whereas IFIX and AIM2 associated with distinct complexes related to antiviral responses, DNA damage responses (DDR), and chromatin remodeling.


The functional interactome of PYHIN immune regulators reveals IFIX is a sensor of viral DNA.

Diner BA, Li T, Greco TM, Crow MS, Fuesler JA, Wang J, Cristea IM - Mol. Syst. Biol. (2015)

The interaction network of the PYHIN protein family345 SAINT-filtered PYHIN–prey protein interactions, common between N- and C-terminally tagged PYHIN isolations, were assessed using the STRING database and visualized in Cytoscape. GO terms were assigned to individual prey nodes and color-coded based on assigned molecular functions (key, bottom left). The number of PYHIN proteins found to interact with a particular prey is represented by the prey node shape (key, bottom right). Known complexes are annotated and network edges indicate interactions with either a PYHIN protein or other prey proteins. Edgeless nodes are arranged in clusters closest to the PYHIN protein(s) with which they interact.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4358659&req=5

fig03: The interaction network of the PYHIN protein family345 SAINT-filtered PYHIN–prey protein interactions, common between N- and C-terminally tagged PYHIN isolations, were assessed using the STRING database and visualized in Cytoscape. GO terms were assigned to individual prey nodes and color-coded based on assigned molecular functions (key, bottom left). The number of PYHIN proteins found to interact with a particular prey is represented by the prey node shape (key, bottom right). Known complexes are annotated and network edges indicate interactions with either a PYHIN protein or other prey proteins. Edgeless nodes are arranged in clusters closest to the PYHIN protein(s) with which they interact.
Mentions: To integrate the putative PYHIN interactions within a network and assess functional complex enrichment, we next searched the SAINT-filtered interactions from all PYHIN isolations against the STRING database of known protein association networks (Szklarczyk et al, 2011). Given the scarcity of information regarding PYHIN interactions and to avoid variations from the tag location, we chose to construct the network by illustrating interactions present with both N- and C-terminally tagged PYHIN proteins. These reflected the majority (345 out of 355) of the detected interactions (Supplementary Tables S4, S5 and S6). Individual PYHIN interaction networks were merged via Cytoscape (Shannon et al, 2003), and gene ontology (GO) terms were assigned to all interactions (Fig3 and Supplementary File S1). The relative enrichment of the proteins isolated with each bait was estimated by calculating a normalized spectral abundance factor (NSAF) for each protein (Zybailov et al, 2007), which was then normalized to the estimated abundance of the protein within the human proteome (PAX values) (Weiss et al, 2010), as we previously reported (Tsai et al, 2012). This analysis highlighted the most enriched SAINT-filtered interactions within the isolation of each PYHIN protein (Supplementary Figs S5, S6, S7 and S8). Interestingly, several prominent functional protein complexes were evident in the PYHIN network (Fig3). Consistent with our hierarchical clustering data, complexes involved in ribosome biogenesis and RNA processing were enriched within IFI16 and MNDA shared networks, whereas IFIX and AIM2 associated with distinct complexes related to antiviral responses, DNA damage responses (DDR), and chromatin remodeling.

Bottom Line: We discover that IFIX detects viral DNA in both the nucleus and cytoplasm, binding foreign DNA via its HIN domain in a sequence-non-specific manner.Furthermore, IFIX contributes to the induction of interferon response.Our results highlight the value of integrative proteomics in deducing protein function and establish IFIX as an antiviral DNA sensor important for mounting immune responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ, USA.

No MeSH data available.


Related in: MedlinePlus