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High definition analysis of host protein stability during human cytomegalovirus infection reveals antiviral factors and viral evasion mechanisms

ABSTRACT: High definition analysis of host protein stability during human cytomegalovirus infection reveals antiviral factors and viral evasion mechanisms

PROVIDER: PRJNA435668 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6765790.fastq.gz	Fastqsanger.gz
	SRR6765782.fastq.gz	Fastqsanger.gz
	SRR6765783.fastq.gz	Fastqsanger.gz
	SRR6765784.fastq.gz	Fastqsanger.gz
	SRR6765785.fastq.gz	Fastqsanger.gz

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High definition analysis of host protein stability during human cytomegalovirus infection reveals antiviral factors and viral evasion mechanisms

Project description:Human cytomegalovirus (HCMV) is an important pathogen with multiple immune evasion strategies, including virally facilitated degradation of host antiviral restriction factors. Here, we describe a multiplexed approach to discover proteins with innate immune function on the basis of active degradation by the proteasome or lysosome during early phase HCMV infection. Using three orthogonal proteomic/transcriptomic screens to quantify protein degradation, with high confidence we identified 35 proteins enriched in antiviral restriction factors. A final screen employed a comprehensive panel of viral mutants to predict viral genes that target >250 human proteins. This approach revealed Helicase-like Transcription Factor (HLTF), a DNA helicase important in DNA repair, potently inhibits early viral gene expression but is rapidly degraded during infection. The functionally unknown HCMV protein UL145 facilitates HLTF degradation by recruiting the Cullin4 E3 ligase complex. Our approach and data will enable further identifications of innate pathways targeted by HCMV and other viruses.

2018-08-16 | GSE111036 | GEO

High definition analysis of protein stability during cytomegalovirus infection informs on cellular restriction

Project description:Human cytomegalovirus (HCMV) is an important pathogen and a paradigm of viral immune evasion. Here, we describe a multiplexed approach to discover proteins with novel innate immune functions on the basis of their active proteasomal or lysosomal degradation during the early phase of HCMV infection. Using three orthogonal proteomic/transcriptomic screens to quantify protein degradation, we identified 35 proteins with high confidence that were enriched in known antiviral restriction factors. A final screen facilitated global analysis of the mechanism of viral immune-modulation by predicting which viral genes target >250 human proteins. Helicase-like Transcription Factor (HLTF), a DNA helicase important in error-free post-replication DNA repair, was rapidly degraded during infection and potently inhibited early viral gene expression. HCMV UL145, a protein of previously unknown function, recruits the Cullin 4 E3 ligase complex to degrade HLTF. Our approach and data will enable further identifications of innate pathways targeted by HCMV and other viruses.

2018-08-16 | PXD009945 | Pride

High-Definition Analysis of Host Protein Stability during Human Cytomegalovirus Infection Reveals Antiviral Factors and Viral Evasion Mechanisms.

Project description:Human cytomegalovirus (HCMV) is an important pathogen with multiple immune evasion strategies, including virally facilitated degradation of host antiviral restriction factors. Here, we describe a multiplexed approach to discover proteins with innate immune function on the basis of active degradation by the proteasome or lysosome during early-phase HCMV infection. Using three orthogonal proteomic/transcriptomic screens to quantify protein degradation, with high confidence we identified 35 proteins enriched in antiviral restriction factors. A final screen employed a comprehensive panel of viral mutants to predict viral genes that target >250 human proteins. This approach revealed that helicase-like transcription factor (HLTF), a DNA helicase important in DNA repair, potently inhibits early viral gene expression but is rapidly degraded during infection. The functionally unknown HCMV protein UL145 facilitates HLTF degradation by recruiting the Cullin4 E3 ligase complex. Our approach and data will enable further identifications of innate pathways targeted by HCMV and other viruses.

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Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex

Project description:Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of viral immune evasion, targeting intrinsic, innate and adaptive immunity. We have employed two novel, orthogonal multiplexed tandem mass tag-based proteomic screens to identify host proteins downregulated by viral factors expressed during the latest phases of viral infection. This approach revealed that the HIV-1 restriction factor Schlafen-11 (SLFN11) was degraded by the poorly characterised, late-expressed HCMV protein RL1, via recruitment of the Cullin4-RING E3 Ubiquitin Ligase (CRL4) complex. SLFN11 potently restricted HCMV infection, inhibiting the formation and spread of viral plaques. Overall, we show that a restriction factor previously thought only to inhibit RNA viruses additionally restricts HCMV. We define the mechanism of viral antagonism and also describe an important resource for revealing additional molecules of importance in antiviral innate immunity and viral immune evasion.

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Evasion of cellular antiviral responses by human cytomegalovirus TRS1 and IRS1.

Project description:During infection with human cytomegalovirus (HCMV), cellular protein synthesis continues even as viral proteins are being synthesized in abundance. Thus, HCMV may have a mechanism for counteracting host cell antiviral pathways that act by shutting off translation. Consistent with this view, HCMV infection of human fibroblasts rescues the replication of a vaccinia virus mutant lacking the double-stranded RNA-binding protein gene E3L (VVdeltaE3L). HCMV also prevents the phosphorylation of the eukaryotic translation initiation factor eIF-2alpha, the activation of RNase L, and the shutoff of viral and cellular protein synthesis that otherwise result from VVdeltaE3L infection. To identify the HCMV gene(s) responsible for these effects, we prepared a library of VVdeltaE3L recombinants containing HCMV genomic fragments. By infecting nonpermissive cells with this library and screening for VV gene expression and replication, we isolated a virus containing a 2.8-kb HCMV fragment that rescues replication of VVdeltaE3L. The fragment comprises the 3' end of the J1S open reading frame through the entire TRS1 gene. Analyses of additional VVdeltaE3L recombinants revealed that the protein encoded by TRS1, pTRS1, as well as the closely related IRS1 gene, rescues VVdeltaE3L replication and prevent the shutoff of protein synthesis, the phosphorylation of eIF-2alpha, and activation of RNase L. These results demonstrate that TRS1 and IRS1 are able to counteract critical host cell antiviral response pathways.

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Human cytomegalovirus-induced host protein citrullination is crucial for viral replication

Project description:Citrullination is the conversion of arginine-to-citrulline by protein arginine deiminases (PADs), whose dysregulation is implicated in the pathogenesis of various types of cancers and autoimmune diseases. Consistent with the ability of human cytomegalovirus (HCMV) to induce post-translational modifications of cellular proteins to gain a survival advantage, we show that HCMV infection of primary human fibroblasts triggers PAD-mediated citrullination of several host proteins, and that this activity promotes viral fitness. Citrullinome analysis reveals significant changes in deimination levels of both cellular and viral proteins, with interferon (IFN)-inducible protein IFIT1 being the most heavily deiminated one. As genetic depletion of IFIT1 strongly enhances HCMV growth, and in vitro IFIT1 citrullination impairs its ability to bind to 5’-pppRNA, we propose that viral-induced IFIT1 citrullination is a novel mechanism of HCMV evasion from host antiviral resistance. Overall, our findings point to a crucial role of citrullination in subverting cellular responses to viral infection.

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Human cytomegalovirus-induced host protein citrullination is crucial for viral replication

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