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Host-pathogen interactome mapping for HTLV-1 and -2 retroviruses.

Simonis N, Rual JF, Lemmens I, Boxus M, Hirozane-Kishikawa T, Gatot JS, Dricot A, Hao T, Vertommen D, Legros S, Daakour S, Klitgord N, Martin M, Willaert JF, Dequiedt F, Navratil V, Cusick ME, Burny A, Van Lint C, Hill DE, Tavernier J, Kettmann R, Vidal M, Twizere JC - Retrovirology (2012)

Bottom Line: Among the 166 interactions identified, 87 and 79 involved HTLV-1 and HTLV-2 -encoded proteins, respectively.Targets for HTLV-1 and HTLV-2 proteins implicate a diverse set of cellular processes including the ubiquitin-proteasome system, the apoptosis, different cancer pathways and the Notch signaling pathway.This study constitutes a first pass, with homogeneous data, at comparative analysis of host targets for HTLV-1 and -2 retroviruses, complements currently existing data for formulation of systems biology models of retroviral induced diseases and presents new insights on biological pathways involved in retroviral infection.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Ave,, Boston, MA 02215, USA.

ABSTRACT

Background: Human T-cell leukemia virus type 1 (HTLV-1) and type 2 both target T lymphocytes, yet induce radically different phenotypic outcomes. HTLV-1 is a causative agent of Adult T-cell leukemia (ATL), whereas HTLV-2, highly similar to HTLV-1, causes no known overt disease. HTLV gene products are engaged in a dynamic struggle of activating and antagonistic interactions with host cells. Investigations focused on one or a few genes have identified several human factors interacting with HTLV viral proteins. Most of the available interaction data concern the highly investigated HTLV-1 Tax protein. Identifying shared and distinct host-pathogen protein interaction profiles for these two viruses would enlighten how they exploit distinctive or common strategies to subvert cellular pathways toward disease progression.

Results: We employ a scalable methodology for the systematic mapping and comparison of pathogen-host protein interactions that includes stringent yeast two-hybrid screening and systematic retest, as well as two independent validations through an additional protein interaction detection method and a functional transactivation assay. The final data set contained 166 interactions between 10 viral proteins and 122 human proteins. Among the 166 interactions identified, 87 and 79 involved HTLV-1 and HTLV-2 -encoded proteins, respectively. Targets for HTLV-1 and HTLV-2 proteins implicate a diverse set of cellular processes including the ubiquitin-proteasome system, the apoptosis, different cancer pathways and the Notch signaling pathway.

Conclusions: This study constitutes a first pass, with homogeneous data, at comparative analysis of host targets for HTLV-1 and -2 retroviruses, complements currently existing data for formulation of systems biology models of retroviral induced diseases and presents new insights on biological pathways involved in retroviral infection.

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Targeting of the Notch signalling pathway by viral proteins. (A) Big diamonds: viral ORFs, with HTLV-1 and HTLV-2 in blue and light blue, respectively. Small circles: human ORFs with green representing membership of the Notch pathway. Grey links: human-human PPIs; blue links: virus-human PPIs. (B) Relative HTLV1-HBZ, -Gag and -Tax mRNA expression following MT4 cells treatment with or without 1 μM of γ-secretase inhibitor L685,458. Viral mRNA expression data are calculated relative to GAPDH mRNA expression data as 2^(CT(GAPDH)-CT(HBZ/Gag/Tax)) over three times triplicate experiments for each gene.
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Figure 10: Targeting of the Notch signalling pathway by viral proteins. (A) Big diamonds: viral ORFs, with HTLV-1 and HTLV-2 in blue and light blue, respectively. Small circles: human ORFs with green representing membership of the Notch pathway. Grey links: human-human PPIs; blue links: virus-human PPIs. (B) Relative HTLV1-HBZ, -Gag and -Tax mRNA expression following MT4 cells treatment with or without 1 μM of γ-secretase inhibitor L685,458. Viral mRNA expression data are calculated relative to GAPDH mRNA expression data as 2^(CT(GAPDH)-CT(HBZ/Gag/Tax)) over three times triplicate experiments for each gene.

Mentions: The highly conserved Notch signaling pathway regulates diverse cell fate decisions, including differentiation, proliferation, communication and specification. Several members of the Notch signaling pathway, including Numb [64], dishevelled (Dvl) proteins [65], cAMP-response element-binding protein (CREB)-binding protein (CREBBP or CBP) [66,67], and p300 [68], are targeted by HTLV Tax, Rex, Hbz, Gag and Pol proteins (Figure 10). It has been recently shown that the γ-secretase inhibitor (GSI) reduced tumor cell proliferation and tumor formation in an Adult T-cell Leukemia animal model [69]. To directly assess the involvement of the Notch pathway in viral infection, we treated an HTLV-1 transformed cell line (MT4) with a γ-secretase inhibitor (GSI) (L-685,458) [70] and tested whether inhibition of the Notch pathway could affect HTLV-1 expression in MT4 cell line. Interestingly, we showed by quantitative RT-PCR, that inhibition of the Notch pathway significantly lowered HTLV-1 HBZ (p < 2.1E-5), Gag (p < 0.04) and Tax1 (p < 0.003) expression in MT4 cells (Figure 10B), suggesting that GSI could be a new class of retroviral replication inhibitors.


Host-pathogen interactome mapping for HTLV-1 and -2 retroviruses.

Simonis N, Rual JF, Lemmens I, Boxus M, Hirozane-Kishikawa T, Gatot JS, Dricot A, Hao T, Vertommen D, Legros S, Daakour S, Klitgord N, Martin M, Willaert JF, Dequiedt F, Navratil V, Cusick ME, Burny A, Van Lint C, Hill DE, Tavernier J, Kettmann R, Vidal M, Twizere JC - Retrovirology (2012)

Targeting of the Notch signalling pathway by viral proteins. (A) Big diamonds: viral ORFs, with HTLV-1 and HTLV-2 in blue and light blue, respectively. Small circles: human ORFs with green representing membership of the Notch pathway. Grey links: human-human PPIs; blue links: virus-human PPIs. (B) Relative HTLV1-HBZ, -Gag and -Tax mRNA expression following MT4 cells treatment with or without 1 μM of γ-secretase inhibitor L685,458. Viral mRNA expression data are calculated relative to GAPDH mRNA expression data as 2^(CT(GAPDH)-CT(HBZ/Gag/Tax)) over three times triplicate experiments for each gene.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351729&req=5

Figure 10: Targeting of the Notch signalling pathway by viral proteins. (A) Big diamonds: viral ORFs, with HTLV-1 and HTLV-2 in blue and light blue, respectively. Small circles: human ORFs with green representing membership of the Notch pathway. Grey links: human-human PPIs; blue links: virus-human PPIs. (B) Relative HTLV1-HBZ, -Gag and -Tax mRNA expression following MT4 cells treatment with or without 1 μM of γ-secretase inhibitor L685,458. Viral mRNA expression data are calculated relative to GAPDH mRNA expression data as 2^(CT(GAPDH)-CT(HBZ/Gag/Tax)) over three times triplicate experiments for each gene.
Mentions: The highly conserved Notch signaling pathway regulates diverse cell fate decisions, including differentiation, proliferation, communication and specification. Several members of the Notch signaling pathway, including Numb [64], dishevelled (Dvl) proteins [65], cAMP-response element-binding protein (CREB)-binding protein (CREBBP or CBP) [66,67], and p300 [68], are targeted by HTLV Tax, Rex, Hbz, Gag and Pol proteins (Figure 10). It has been recently shown that the γ-secretase inhibitor (GSI) reduced tumor cell proliferation and tumor formation in an Adult T-cell Leukemia animal model [69]. To directly assess the involvement of the Notch pathway in viral infection, we treated an HTLV-1 transformed cell line (MT4) with a γ-secretase inhibitor (GSI) (L-685,458) [70] and tested whether inhibition of the Notch pathway could affect HTLV-1 expression in MT4 cell line. Interestingly, we showed by quantitative RT-PCR, that inhibition of the Notch pathway significantly lowered HTLV-1 HBZ (p < 2.1E-5), Gag (p < 0.04) and Tax1 (p < 0.003) expression in MT4 cells (Figure 10B), suggesting that GSI could be a new class of retroviral replication inhibitors.

Bottom Line: Among the 166 interactions identified, 87 and 79 involved HTLV-1 and HTLV-2 -encoded proteins, respectively.Targets for HTLV-1 and HTLV-2 proteins implicate a diverse set of cellular processes including the ubiquitin-proteasome system, the apoptosis, different cancer pathways and the Notch signaling pathway.This study constitutes a first pass, with homogeneous data, at comparative analysis of host targets for HTLV-1 and -2 retroviruses, complements currently existing data for formulation of systems biology models of retroviral induced diseases and presents new insights on biological pathways involved in retroviral infection.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Ave,, Boston, MA 02215, USA.

ABSTRACT

Background: Human T-cell leukemia virus type 1 (HTLV-1) and type 2 both target T lymphocytes, yet induce radically different phenotypic outcomes. HTLV-1 is a causative agent of Adult T-cell leukemia (ATL), whereas HTLV-2, highly similar to HTLV-1, causes no known overt disease. HTLV gene products are engaged in a dynamic struggle of activating and antagonistic interactions with host cells. Investigations focused on one or a few genes have identified several human factors interacting with HTLV viral proteins. Most of the available interaction data concern the highly investigated HTLV-1 Tax protein. Identifying shared and distinct host-pathogen protein interaction profiles for these two viruses would enlighten how they exploit distinctive or common strategies to subvert cellular pathways toward disease progression.

Results: We employ a scalable methodology for the systematic mapping and comparison of pathogen-host protein interactions that includes stringent yeast two-hybrid screening and systematic retest, as well as two independent validations through an additional protein interaction detection method and a functional transactivation assay. The final data set contained 166 interactions between 10 viral proteins and 122 human proteins. Among the 166 interactions identified, 87 and 79 involved HTLV-1 and HTLV-2 -encoded proteins, respectively. Targets for HTLV-1 and HTLV-2 proteins implicate a diverse set of cellular processes including the ubiquitin-proteasome system, the apoptosis, different cancer pathways and the Notch signaling pathway.

Conclusions: This study constitutes a first pass, with homogeneous data, at comparative analysis of host targets for HTLV-1 and -2 retroviruses, complements currently existing data for formulation of systems biology models of retroviral induced diseases and presents new insights on biological pathways involved in retroviral infection.

Show MeSH
Related in: MedlinePlus