Human T-cell leukemia virus type I (HTLV-I) infection and the onset of adult T-cell leukemia (ATL)

Matsuoka, Masao

doi:10.1186/1742-4690-2-27

Cited by 131 publications

(55 citation statements)

References 128 publications

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“…Similarly, 29% of SUN2-overexpressing cells had nuclei with circularity values below 0.4, whereas the values were Ͻ1% for control cells. Similar flower-like nuclei have been reported previously, both in cells from patients with adult T-cell leukemia (ATL) (55,56) or with progeria (57) and in cell lines overexpressing FEZ1 (58) or Csk homologous kinase (Chk) (59).…”

Section: Sun2supporting

confidence: 62%

SUN2 Overexpression Deforms Nuclear Shape and Inhibits HIV

Donahue

Amraoui

Nunzio

et al. 2016

J Virol

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In a previous screen of putative interferon-stimulated genes, SUN2 was shown to inhibit HIV-1 infection in an uncharacterized manner. SUN2 is an inner nuclear membrane protein belonging to the linker of nucleoskeleton and cytoskeleton complex. We have analyzed here the role of SUN2 in HIV infection. We report that in contrast to what was initially thought, SUN2 is not induced by type I interferon, and that SUN2 silencing does not modulate HIV infection. However, SUN2 overexpression in cell lines and in primary monocyte-derived dendritic cells inhibits the replication of HIV but not murine leukemia virus or chikungunya virus. We identified HIV-1 and HIV-2 strains that are unaffected by SUN2, suggesting that the effect is specific to particular viral components or cofactors. Intriguingly, SUN2 overexpression induces a multilobular flower-like nuclear shape that does not impact cell viability and is similar to that of cells isolated from patients with HTLV-I-associated adult T-cell leukemia or with progeria. Nuclear shape changes and HIV inhibition both mapped to the nucleoplasmic domain of SUN2 that interacts with the nuclear lamina. This block to HIV replication occurs between reverse transcription and nuclear entry, and passaging experiments selected for a single-amino-acid change in capsid (CA) that leads to resistance to overexpressed SUN2. Furthermore, using chemical inhibition or silencing of cyclophilin A (CypA), as well as CA mutant viruses, we implicated CypA in the SUN2-imposed block to HIV infection. Our results demonstrate that SUN2 overexpression perturbs both nuclear shape and early events of HIV infection. IMPORTANCECells encode proteins that interfere with viral replication, a number of which have been identified in overexpression screens. SUN2 is a nuclear membrane protein that was shown to inhibit HIV infection in such a screen, but how it blocked HIV infection was not known. We show that SUN2 overexpression blocks the infection of certain strains of HIV before nuclear entry. Mutation of the viral capsid protein yielded SUN2-resistant HIV. Additionally, the inhibition of HIV infection by SUN2 involves cyclophilin A, a protein that binds the HIV capsid and directs subsequent steps of infection. We also found that SUN2 overexpression substantially changes the shape of the cell's nucleus, resulting in many flower-like nuclei. Both HIV inhibition and deformation of nuclear shape required the domain of SUN2 that interacts with the nuclear lamina. Our results demonstrate that SUN2 interferes with HIV infection and highlight novel links between nuclear shape and viral infection.

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Section: Sun2supporting

confidence: 62%

SUN2 Overexpression Deforms Nuclear Shape and Inhibits HIV

Donahue

Amraoui

Nunzio

et al. 2016

J Virol

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“…Tax has pleiotropic actions by interacting with cellular proteins, which promotes clonal proliferation of infected cells (2, 3). However, the role of the tax gene remains an enigma in ATL cells, because tax gene transcripts cannot be detected in Ϸ60% of ATL cases (12). However, the 3Ј LTR and HBZ sequences are conserved in all ATL cells regardless of deletion or hypermethylation of the 5Ј LTR or of genetic changes in the tax gene, suggesting that an intact 3Ј LTR and HBZ gene are critical for oncogenesis.…”

Section: In Vivo Effect Of Hbz Gene Expression In Transgenic Micementioning

confidence: 99%

“…In addition, Tax can functionally inactivate p53 (9), resulting in inhibition of apoptosis. Thus, Tax promotes proliferation and suppresses apoptosis of infected cells, leading to clonal proliferation (10)(11)(12). As a consequence, HTLV-I causes ATL, a fatal neoplastic disease of CD4-positive T-lymphocytes.…”

Section: Fig 1 Hbz Gene Expression In Atl Cells (A) 5јmentioning

confidence: 99%

HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells

Satou

Yasunaga

Yoshida

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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526

760

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Human T cell leukemia virus type I (HTLV-I) causes adult T cell leukemia (ATL) in 2–5% of carriers after a long latent period. An HTLV-I encoded protein, Tax, induces proliferation and inhibits apoptosis, resulting in clonal proliferation of infected cells. However, tax gene expression in ATL cells is disrupted by several mechanisms, including genetic changes in the tax gene and DNA methylation/deletion of the 5′ long terminal repeat (LTR). Because Tax is the major target of cytotoxic T-lymphocytes in vivo , loss of Tax expression should enable ATL cells to escape the host immune system. The 5′ LTR of HTLV-I is frequently hypermethylated or deleted in ATL cells, whereas the 3′ LTR remains unmethylated and intact, suggesting the involvement of the 3′ LTR in leukemogenesis. Here we show that a gene encoded by the minus strand of the HTLV-I proviral genome, HTLV-I basic leucine zipper factor ( HBZ ), is transcribed from 3′-LTR in all ATL cells. Suppression of HBZ gene transcription by short interfering RNA inhibits proliferation of ATL cells. In addition, HBZ gene expression promotes proliferation of a human T cell line. Analyses of T cell lines transfected with mutated HBZ genes showed that HBZ promotes T cell proliferation in its RNA form, whereas HBZ protein suppresses Tax-mediated viral transcription through the 5′ LTR. Thus, the single HBZ gene has bimodal functions in two different molecular forms. The growth-promoting activity of HBZ RNA likely plays an important role in oncogenesis by HTLV-I.

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“…When treated with such drugs, human cells halted mitosis while rodent cells continued to progress and exited mitosis. As we are interested in how HTLV-1-transformed cells (reviewed in Matsuoka, 2005;Azran et al, 2004) respond to microtubule depolymerizing agents , we revisited Schimke and co-workers' original observations in an attempt to find a molecular explanation.…”

Section: Resultsmentioning

confidence: 99%

The N-terminus of rodent and human MAD1 confers species-specific stringency to spindle assembly checkpoint

et al. 2005

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The spindle assembly checkpoint (SAC) guards against chromosomal mis-segregation and the emergence of aneuploidy. SAC in higher eukaryotes includes at least 10 proteins including MAD1-3, BUB1-3, and Msp1. A long-standing observation has been that rodent cells are more tolerant of microtubule toxins than primate cells indicating that SAC function is more relaxed in the former than the latter. Here, we report on an unexpected functional difference between the rodent and human MAD1 component of the respective SAC. Ectopic expression of human MAD1 in mouse and hamster cells corrected a relaxed SAC to a more stringent form. Our findings posit MAD1 as a species-specific determinant which influences the stringency of cellular response to microtubule depolymerization and spindle damage.

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Human T-cell leukemia virus type I (HTLV-I) infection and the onset of adult T-cell leukemia (ATL)

Cited by 131 publications

References 128 publications

SUN2 Overexpression Deforms Nuclear Shape and Inhibits HIV

SUN2 Overexpression Deforms Nuclear Shape and Inhibits HIV

HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells

The N-terminus of rodent and human MAD1 confers species-specific stringency to spindle assembly checkpoint

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