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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 Ubiquitin-mediated proteolysis pathway by viral proteins. Schematic representation of PPIs. 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 Ubiquitin-mediated proteolysis pathway. Grey links: human-human PPIs; blue links: virus-human PPIs.
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Figure 9: Targeting of the Ubiquitin-mediated proteolysis pathway by viral proteins. Schematic representation of PPIs. 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 Ubiquitin-mediated proteolysis pathway. Grey links: human-human PPIs; blue links: virus-human PPIs.

Mentions: We identified cellular E2 ubiquitin-conjugating enzymes UBE2I and UBE2N or UBC13; and E3 SUMO-protein ligases PIAS (protein inhibitor of activated STAT) 1, 2 and 4. Both types of enzymes have been previously shown to play a role in Tax-mediated NF-kB activation [50,51]. KEGG analysis also highlighted E3 ubiquitin ligases (CDC23, TRAF2 and TRAF6), which interact with HTLV proteins and which may play important roles in induced perturbations of the proteasomal pathway. CDC23 is a member of the anaphase promoting complex/cyclosome (APC/C, including CDC23), an E3 ubiquitin ligase that controls metaphase to anaphase transition [52-54]. TRAF proteins contain a RING finger domain, a domain that can simultaneously bind ubiquitination enzymes and their substrates [55,56] (Figure 9). HTLV-1 Tax might also provide a bridge to the proteasome by disrupting the interaction between an E3 ubiquitin ligase and its substrate, illustrated by the inactivation by Tax of the A20-Itch E3 ligase complex, potentially leading to a permanent activation of tumor necrosis factor (TNF) receptor (TNFR) signaling [57].


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 Ubiquitin-mediated proteolysis pathway by viral proteins. Schematic representation of PPIs. 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 Ubiquitin-mediated proteolysis pathway. Grey links: human-human PPIs; blue links: virus-human PPIs.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 9: Targeting of the Ubiquitin-mediated proteolysis pathway by viral proteins. Schematic representation of PPIs. 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 Ubiquitin-mediated proteolysis pathway. Grey links: human-human PPIs; blue links: virus-human PPIs.
Mentions: We identified cellular E2 ubiquitin-conjugating enzymes UBE2I and UBE2N or UBC13; and E3 SUMO-protein ligases PIAS (protein inhibitor of activated STAT) 1, 2 and 4. Both types of enzymes have been previously shown to play a role in Tax-mediated NF-kB activation [50,51]. KEGG analysis also highlighted E3 ubiquitin ligases (CDC23, TRAF2 and TRAF6), which interact with HTLV proteins and which may play important roles in induced perturbations of the proteasomal pathway. CDC23 is a member of the anaphase promoting complex/cyclosome (APC/C, including CDC23), an E3 ubiquitin ligase that controls metaphase to anaphase transition [52-54]. TRAF proteins contain a RING finger domain, a domain that can simultaneously bind ubiquitination enzymes and their substrates [55,56] (Figure 9). HTLV-1 Tax might also provide a bridge to the proteasome by disrupting the interaction between an E3 ubiquitin ligase and its substrate, illustrated by the inactivation by Tax of the A20-Itch E3 ligase complex, potentially leading to a permanent activation of tumor necrosis factor (TNF) receptor (TNFR) signaling [57].

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