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Contribution of IFIX to nuclear and cytoplasmic proteome changes during immune signaling

ABSTRACT: IFIX is a nuclear DNA sensor that is known to induce cytokine expression in response to both cytoplasmic DNA and foreign DNA in the nucleus. Here, we examine the concomitant nuclear and cytoplasmic proteome changes that are driven by IFIX during immune response to viral infection and transfection of viral DNA. Furthermore, we identify the posttranslational modifications present on the IFIX protein during HSV-1 infection.

INSTRUMENT(S): LTQ Orbitrap Velos, Q Exactive HF

ORGANISM(S): Homo Sapiens (human) Human Alphaherpesvirus 1

TISSUE(S): Primary Cell, Cell Culture, Fibroblast

SUBMITTER: Tim Howard

LAB HEAD: Ileana M Cristea

PROVIDER: PXD025101 | Pride | 2021-06-02

REPOSITORIES: Pride

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			Action	DRS
	20160924_IFIX_WT-HSV1_01.msf	Msf
	20160924_IFIX_WT-HSV1_01.raw	Raw
	20160924_IFIX_WT-HSV1_02.msf	Msf
	20160924_IFIX_WT-HSV1_02.raw	Raw
	20160924_IFIX_WT-HSV1_03.msf	Msf

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Project description:Rapid and dynamically shifting protein-protein interactions (PPIs) underlie the capacity of cells to recognize viral infections and ignite the downstream cascades that constitute the innate-immune response. Herpesviruses share an ancient history of coevolution with their hosts and have developed reciprocal methods to suppress or hijack immune response proteins — underscoring the biological complexity of host-pathogen interactions during the immune response. Accordingly, conventional approaches to studying PPIs downstream of innate immune sensing fail to capture both the global scope and the dynamic on-off behavior of protein complexes as they are altered throughout cellular space and time. To overcome this barrier, we have applied Thermal Proteome Profiling Mass Spectrometry (TPP-MS) to systemically characterize PPIs that coordinate the innate-immune response to Herpes Simplex Virus 1 (HSV-1) infection in primary human fibroblasts. Further, by advancing the power of thermal protein co ggregation analysis (TPCA) to infer associations de novo and to globally track these PPIs, we developed a time-resolved portrait of cellular and viral protein associations with IFI16, a nuclear DNA sensor that serves as a central platform for HSV-1 immune responses. Our TPCA analysis, along with high-resolution microscopy and molecular virological techniques, linked IFI16 sensing of viral DNA in the nuclear periphery to the master DNA damage response (DDR) regulatory kinase, DNA-PK — the activation of which we show to be necessary for the antiviral and inflammatory responses to infection. Finally, phospho-peptide enrichment and MS analysis of DNA-PK substrates revealed IFI16 to be targeted by DNA-PK after both DNA damage and viral infection. Functional analysis of this DDR-dependent IFI16 phosphorylation revealed the specific modified residue required for IFI16-driven cytokine responses. Altogether, our study represents the first systems-wide characterization of the global dynamics of PPIs during HSV-1 infection and uncovers a missing link in the immune signaling pathway that places IFI16 and DNA-PK at the center of herpesvirus innate immunity.

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Contribution of IFIX to nuclear and cytoplasmic proteome changes during immune signaling

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