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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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Comparison to reported PPIs. (A) Overlap between HTLV human targets curated from the literature (rows) and from our Y2H screen (columns). For each virus, the number directly below (columns) or beside (rows) the virus names gives the total number of human targets. The center shows the number of shared human targets between literature and our study. (B) Human proteins interacting with multiple viral proteins. Grey circles: human proteins, Blue edges: PPIs from literature curation; grey edges: Y2H PPIs found in our screen; magenta edge: PPIs found in our Y2H screen and literature curation.
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Figure 4: Comparison to reported PPIs. (A) Overlap between HTLV human targets curated from the literature (rows) and from our Y2H screen (columns). For each virus, the number directly below (columns) or beside (rows) the virus names gives the total number of human targets. The center shows the number of shared human targets between literature and our study. (B) Human proteins interacting with multiple viral proteins. Grey circles: human proteins, Blue edges: PPIs from literature curation; grey edges: Y2H PPIs found in our screen; magenta edge: PPIs found in our Y2H screen and literature curation.

Mentions: Databases dedicated to virus-host PPIs (VirHostNet and VirusMint) contain only few PPI related to HTLV viruses. We thus manually curated the literature and found that most of host factors, which have been demonstrated to interact with HTLV proteins, concern the highly investigated HTLV-1 Tax (122/147) (Additional file 1: Table S5). The overlap between our study and known data is sparse (3 proteins: Nup62, MAD1L1 and Cdc23 - Figure 4A), not surprising given the use of dissimilar methods, clones, and search spaces. We integrated our dataset with current literature data on known human-HTLV PPIs and highlighted host factors interacting with at least two different viral proteins (Figure 4B). As examples, HTLV-1 HBZ, Tax and HTLV-2 APH-2 interact with CREB. Both HTLV-1 HBZ and Tax proteins interact with AP-1, CBP/p300, CREB, ATF and p65 NFκB transcription factors. However, interaction with these host factors drives opposite effects, as HBZ and APH-2 are involved in the repression of HTLV-transcription and are always expressed in leukemic cells [33,34].


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)

Comparison to reported PPIs. (A) Overlap between HTLV human targets curated from the literature (rows) and from our Y2H screen (columns). For each virus, the number directly below (columns) or beside (rows) the virus names gives the total number of human targets. The center shows the number of shared human targets between literature and our study. (B) Human proteins interacting with multiple viral proteins. Grey circles: human proteins, Blue edges: PPIs from literature curation; grey edges: Y2H PPIs found in our screen; magenta edge: PPIs found in our Y2H screen and literature curation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Comparison to reported PPIs. (A) Overlap between HTLV human targets curated from the literature (rows) and from our Y2H screen (columns). For each virus, the number directly below (columns) or beside (rows) the virus names gives the total number of human targets. The center shows the number of shared human targets between literature and our study. (B) Human proteins interacting with multiple viral proteins. Grey circles: human proteins, Blue edges: PPIs from literature curation; grey edges: Y2H PPIs found in our screen; magenta edge: PPIs found in our Y2H screen and literature curation.
Mentions: Databases dedicated to virus-host PPIs (VirHostNet and VirusMint) contain only few PPI related to HTLV viruses. We thus manually curated the literature and found that most of host factors, which have been demonstrated to interact with HTLV proteins, concern the highly investigated HTLV-1 Tax (122/147) (Additional file 1: Table S5). The overlap between our study and known data is sparse (3 proteins: Nup62, MAD1L1 and Cdc23 - Figure 4A), not surprising given the use of dissimilar methods, clones, and search spaces. We integrated our dataset with current literature data on known human-HTLV PPIs and highlighted host factors interacting with at least two different viral proteins (Figure 4B). As examples, HTLV-1 HBZ, Tax and HTLV-2 APH-2 interact with CREB. Both HTLV-1 HBZ and Tax proteins interact with AP-1, CBP/p300, CREB, ATF and p65 NFκB transcription factors. However, interaction with these host factors drives opposite effects, as HBZ and APH-2 are involved in the repression of HTLV-transcription and are always expressed in leukemic cells [33,34].

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