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Identification of FAM111A as an SV40 host range restriction and adenovirus helper factor.

Fine DA, Rozenblatt-Rosen O, Padi M, Korkhin A, James RL, Adelmant G, Yoon R, Guo L, Berrios C, Zhang Y, Calderwood MA, Velmurgan S, Cheng J, Marto JA, Hill DE, Cusick ME, Vidal M, Florens L, Washburn MP, Litovchick L, DeCaprio JA - PLoS Pathog. (2012)

Bottom Line: The SV40 large T antigen (LT) contains several discrete functional domains including the LXCXE or RB-binding motif, the DNA binding and helicase domains that contribute to the viral life cycle.To understand how LT affects the host cell to facilitate viral replication, we expressed full-length or functional domains of LT in cells, identified interacting host proteins and carried out expression profiling.FAM111A functions as a host range restriction factor that is specifically targeted by SV40 LT.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

ABSTRACT
The small genome of polyomaviruses encodes a limited number of proteins that are highly dependent on interactions with host cell proteins for efficient viral replication. The SV40 large T antigen (LT) contains several discrete functional domains including the LXCXE or RB-binding motif, the DNA binding and helicase domains that contribute to the viral life cycle. In addition, the LT C-terminal region contains the host range and adenovirus helper functions required for lytic infection in certain restrictive cell types. To understand how LT affects the host cell to facilitate viral replication, we expressed full-length or functional domains of LT in cells, identified interacting host proteins and carried out expression profiling. LT perturbed the expression of p53 target genes and subsets of cell-cycle dependent genes regulated by the DREAM and the B-Myb-MuvB complexes. Affinity purification of LT followed by mass spectrometry revealed a specific interaction between the LT C-terminal region and FAM111A, a previously uncharacterized protein. Depletion of FAM111A recapitulated the effects of heterologous expression of the LT C-terminal region, including increased viral gene expression and lytic infection of SV40 host range mutants and adenovirus replication in restrictive cells. FAM111A functions as a host range restriction factor that is specifically targeted by SV40 LT.

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LT interactome perturbs host gene expression, overcomes host range restriction and enables viral gene expression.SV40 LT interaction with p130 (RBL2) disrupts the DREAM complex leading to cell cycle entry and increased FAM111A expression. LT reduces the expression of p53-responsive genes. LT binding to FAM111A overcomes SV40 host range restriction and enables the adenovirus helper effect.
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ppat-1002949-g009: LT interactome perturbs host gene expression, overcomes host range restriction and enables viral gene expression.SV40 LT interaction with p130 (RBL2) disrupts the DREAM complex leading to cell cycle entry and increased FAM111A expression. LT reduces the expression of p53-responsive genes. LT binding to FAM111A overcomes SV40 host range restriction and enables the adenovirus helper effect.

Mentions: Proteomic identification of LT associated proteins confirmed several known co-complex associations including p53 and RB (Figure 9). LT bound to all three members of the RB family of proteins. In contrast, LT was unable to bind to any of the MuvB subunit proteins (LIN9, LIN37, LIN54, LIN52, or RBBP4), indicating that LT can disrupt the p130-containing DREAM complex. In keeping with the ability to disrupt the DREAM complex, LT led to increased expression of DREAM target genes (Figure 2B).


Identification of FAM111A as an SV40 host range restriction and adenovirus helper factor.

Fine DA, Rozenblatt-Rosen O, Padi M, Korkhin A, James RL, Adelmant G, Yoon R, Guo L, Berrios C, Zhang Y, Calderwood MA, Velmurgan S, Cheng J, Marto JA, Hill DE, Cusick ME, Vidal M, Florens L, Washburn MP, Litovchick L, DeCaprio JA - PLoS Pathog. (2012)

LT interactome perturbs host gene expression, overcomes host range restriction and enables viral gene expression.SV40 LT interaction with p130 (RBL2) disrupts the DREAM complex leading to cell cycle entry and increased FAM111A expression. LT reduces the expression of p53-responsive genes. LT binding to FAM111A overcomes SV40 host range restriction and enables the adenovirus helper effect.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3475652&req=5

ppat-1002949-g009: LT interactome perturbs host gene expression, overcomes host range restriction and enables viral gene expression.SV40 LT interaction with p130 (RBL2) disrupts the DREAM complex leading to cell cycle entry and increased FAM111A expression. LT reduces the expression of p53-responsive genes. LT binding to FAM111A overcomes SV40 host range restriction and enables the adenovirus helper effect.
Mentions: Proteomic identification of LT associated proteins confirmed several known co-complex associations including p53 and RB (Figure 9). LT bound to all three members of the RB family of proteins. In contrast, LT was unable to bind to any of the MuvB subunit proteins (LIN9, LIN37, LIN54, LIN52, or RBBP4), indicating that LT can disrupt the p130-containing DREAM complex. In keeping with the ability to disrupt the DREAM complex, LT led to increased expression of DREAM target genes (Figure 2B).

Bottom Line: The SV40 large T antigen (LT) contains several discrete functional domains including the LXCXE or RB-binding motif, the DNA binding and helicase domains that contribute to the viral life cycle.To understand how LT affects the host cell to facilitate viral replication, we expressed full-length or functional domains of LT in cells, identified interacting host proteins and carried out expression profiling.FAM111A functions as a host range restriction factor that is specifically targeted by SV40 LT.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

ABSTRACT
The small genome of polyomaviruses encodes a limited number of proteins that are highly dependent on interactions with host cell proteins for efficient viral replication. The SV40 large T antigen (LT) contains several discrete functional domains including the LXCXE or RB-binding motif, the DNA binding and helicase domains that contribute to the viral life cycle. In addition, the LT C-terminal region contains the host range and adenovirus helper functions required for lytic infection in certain restrictive cell types. To understand how LT affects the host cell to facilitate viral replication, we expressed full-length or functional domains of LT in cells, identified interacting host proteins and carried out expression profiling. LT perturbed the expression of p53 target genes and subsets of cell-cycle dependent genes regulated by the DREAM and the B-Myb-MuvB complexes. Affinity purification of LT followed by mass spectrometry revealed a specific interaction between the LT C-terminal region and FAM111A, a previously uncharacterized protein. Depletion of FAM111A recapitulated the effects of heterologous expression of the LT C-terminal region, including increased viral gene expression and lytic infection of SV40 host range mutants and adenovirus replication in restrictive cells. FAM111A functions as a host range restriction factor that is specifically targeted by SV40 LT.

Show MeSH
Related in: MedlinePlus