Human T-lymphotropic Virus Type 1 p30 Interacts with REG and Modulates ATM (Ataxia Telangiectasia Mutated) to Promote Cell Survival

Center for Retrovirus Research, Ohio State University, Columbus, Ohio 43210, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2011; 286(9):7661-8. DOI: 10.1074/jbc.M110.176354
Source: PubMed


Human T-lymphotropic virus type 1 (HTLV-1) is a causative agent of adult T cell leukemia/lymphoma and a variety of inflammatory
disorders. HTLV-1 encodes a nuclear localizing protein, p30, that selectively alters viral and cellular gene expression, activates
G2-M cell cycle checkpoints, and is essential for viral spread. Here, we used immunoprecipitation and affinity pulldown of ectopically
expressed p30 coupled with mass spectrometry to identify cellular binding partners of p30. Our data indicate that p30 specifically
binds to cellular ATM (ataxia telangiectasia mutated) and REGγ (a nuclear 20 S proteasome activator). Under conditions of genotoxic stress, p30 expression was associated
with reduced levels of ATM and increased cell survival. Knockdown or overexpression of REGγ paralleled p30 expression, suggesting
an unexpected enhancement of p30 expression in the presence of REGγ. Finally, size exclusion chromatography revealed the presence
of p30 in a high molecular mass complex along with ATM and REGγ. On the basis of our findings, we propose that HTLV-1 p30
interacts with ATM and REGγ to increase viral spread by facilitating cell survival.

Full-text preview

Available from:
  • Source
    • "DNA double strand breaks (DSB) are highly toxic to cells and are associated with developmental, immunological, neurological disorders, and various cancers (Jackson and Bartek, 2009; McKinnon, 2009). Anupam et al. (2011) demonstrated that p30 confers a growth advantage to cells that have undergone double-stranded DNA damage. It was shown that p30 interacts with ATM and reduces the levels of ataxia telangiectasia mutated (ATM) and phosphorylated ATM upon double stranded DNA damage. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Extensive studies of human T-cell leukemia virus (HTLV)-1 and HTLV-2 over the last three decades have provided detailed knowledge on viral transformation, host-viral interactions and pathogenesis. HTLV-1 is the etiological agent of adult T cell leukemia and multiple neurodegenerative and inflammatory diseases while HTLV-2 disease association remains elusive, with few infected individuals displaying neurodegenerative diseases similar to HTLV-1. The HTLV group of oncoretroviruses has a genome that encodes structural and enzymatic proteins Gag, Pro, and Env, regulatory proteins Tax and Rex, and several accessory proteins from the pX region. Of these proteins, HTLV-1 p30 and HTLV-2 p28 are encoded by the open reading frame II of the pX region. Like most other accessory proteins, p30 and p28 are dispensable for in vitro viral replication and transformation but are required for efficient viral replication and persistence in vivo. Both p30 and p28 regulate viral gene expression at the post-transcriptional level whereas p30 can also function at the transcriptional level. Recently, several reports have implicated p30 and p28 in multiple cellular processes, which provide novel insight into HTLV spread and survival and ultimately pathogenesis. In this review we summarize and compare what is known about p30 and p28, highlighting their roles in viral replication and viral pathogenesis.
    Full-text · Article · Sep 2013 · Frontiers in Microbiology
  • Source
    • "In this list ATM, PRMT5 and VCL (vinculin) overlapped with the RG list from the exon array and CALD1, LCK and MXI1 overlapped with our AS gene list, thus providing additional evidence for these genes having different products under different conditions. ATM was found to promote T cell survival on interaction with HTLV-I p30 (KEGG pathway hsa05166) [46]. Vinculin (VCL) and caldesmon 1 (CALD1) have established roles in actin cytoskeleton regulation and stabilization during focal adhesion, migration, invasion and proliferation, although this was not yet confirmed to apply to T cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA. Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing. To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression. Applying our algorithm to the data, 9% of the genes were assigned as AS, while only 3% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry. PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell suppression.
    Full-text · Article · Feb 2013 · PLoS ONE
  • Source
    • "Our finding is consistent with the facts that p30 protects cells from camptothecin, a topoisomerase I inhibitor, which induces apoptosis in cells in the S phase of the cell cycle, and irradiation. A recent study also showed that p30 binds to ataxia telangiectasia mutated (ATM) and modulates its phosphorylation to prevent apoptosis (Anupam et al., 2011). In addition to increasing genomic instability, p30 also promotes transformation through enhancing the transcriptional and transforming activity of Myc. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The human T-lymphotropic virus type-1 (HTLV-1) is etiologically linked to adult T cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-1-associated myelopathy. While the role of Tax and Rex in viral replication and pathogenesis has been extensively studied, recent evidence suggests that additional viral proteins are essential for the virus life cycle in vivo. In this review, we will summarize possible molecular mechanisms evoked in the literature to explain how p12, p8, p30, and p13 facilitate persistent viral infection of the host. We will explore several stratagems used by HTLV-1 accessory genes to escape immune surveillance, to establish latency, and to deregulate cell cycle and apoptosis to participate in virus-mediated cellular transformation.
    Full-text · Article · Dec 2012 · Frontiers in Microbiology
Show more