HSP90 Protects the Human T-Cell Leukemia Virus Type 1 (HTLV-1) Tax Oncoprotein from Proteasomal Degradation To Support NF-κB Activation and HTLV-1 Replication

Gao, Linlin; Harhaj, Edward W.

doi:10.1128/jvi.02006-13

Cited by 38 publications

(32 citation statements)

References 70 publications

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“…However, direct inhibition or knockdown of HSP90β and the concomitant reduced expression of MRP‐1 in the mitochondria did not sensitize ES cells to doxorubicin. This may reflect the incomplete inhibition or knockdown of HSP90β, consistent with previous attempts that have failed to completely knock down HSP90β (42). Alternatively, off‐target effects of HSP90 inhibition and knockdown leading to the degradation of client proteins and modification of several signaling pathways (43, 44) may in part explain the lack of sensitization to MRP‐1 substrates.…”

Section: Discussionsupporting

confidence: 82%

Localization of MRP‐1 to the outer mitochondrial membrane by the chaperone protein HSP90β

2015

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Overexpression of plasma membrane multidrug resistance-associated protein 1 (MRP-1) in Ewing's sarcoma (ES) predicts poor outcome. MRP-1 is also expressed in mitochondria, and we have examined the submitochondrial localization of MRP-1 and investigated the mechanism of MRP-1 transport and role of this organelle in the response to doxorubicin. The mitochondrial localization of MRP-1 was examined in ES cell lines by differential centrifugation and membrane solubilization by digitonin. Whether MRP-1 is chaperoned by heat shock proteins (HSPs) was investigated by immunoprecipitation, immunofluorescence microscopy, and HSP knockout using small hairpin RNA and inhibitors (apoptozole, 17-AAG, and NVPAUY). The effect of disrupting mitochondrial MRP-1-dependent efflux activity on the cytotoxic effect of doxorubicin was investigated by counting viable cell number. Mitochondrial MRP-1 is glycosylated and localized to the outer mitochondrial membrane, where it is coexpressed with HSP90. MRP-1 binds to both HSP90 and HSP70, although only inhibition of HSP90β decreases expression of MRP-1 in the mitochondria. Disruption of mitochondrial MRP-1-dependent efflux significantly increases the cytotoxic effect of doxorubicin (combination index, <0.9). For the first time, we have demonstrated that mitochondrial MRP-1 is expressed in the outer mitochondrial membrane and is a client protein of HSP90β, where it may play a role in the doxorubicin-induced resistance of ES.-Roundhill, E., Turnbull, D., Burchill, S. Localization of MRP-1 to the outer mitochondrial membrane by the chaperone protein HSP90β.

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Section: Discussionsupporting

confidence: 82%

Localization of MRP‐1 to the outer mitochondrial membrane by the chaperone protein HSP90β

2015

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“…Together, our data support that niclosamide-mediated degradation of Tax in proteasome is through ubiquitination-dependent mechanism. Considering the controversial reports about maintenance of the Tax stability through ubiquitination [16; 21; 22; 23; 24; 25], further study is necessary to elucidate the mechanism that niclosamide induces ubiquitination of certain cellular proteins and Tax for degradation.…”

Section: Discussionmentioning

confidence: 99%

Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes

Xiang

Yuan

Chen

et al. 2015

Biochemical and Biophysical Research Communications

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Adult T cell leukemia and lymphoma (ATL) is a highly aggressive form of hematological malignancy and is caused by chronic infection of human T cell leukemia virus type 1 (HTLV-1). The viral genome encodes an oncogenic protein, Tax, which plays a key role in transactivating viral gene transcription and in deregulating cellular oncogenic signaling to promote survival, proliferation and transformation of virally infected T cells. Hence, Tax is a desirable therapeutic target, particularly at early stage of HTLV-1-mediated oncogenesis. We here show that niclosamide, an anti-helminthic molecule, induced apoptosis of HTLV-1-transformed T cells. Niclosamide facilitated degradation of the Tax protein in proteasome. Consistent with niclosamide-mediated Tax degradation, this compound inhibited activities of MAPK/ERK1/2 and IκB kinases. In addition, niclosamide downregulated Stat3 and pro-survival Bcl-2 family members such as Mcl-1 and repressed the viral gene transcription of HTLV-1 through induction of Tax degradation. Since Tax, Stat3 and Mcl-1 are crucial molecules for promoting survival and growth of HTLV-1-transformed T cells, our findings demonstrate a novel mechanism of niclosamide in inducing Tax degradation and downregulating various cellular pro-survival molecules, thereby promoting apoptosis of HTLV-1-associated leukemia cells.

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“…A highly dynamic structure and intrinsic disorder were suggested for the Tax-1 protein [115]. Further flexibility can be achieved by its association with chaperones such as Hsp90 (heat shock protein 90) [161] and the prolyl cis-trans-isomerase Pin1 [162], thus increasing the repertoire of binding partners. While the cytosolic events leading to the activation of NF-κB have now reached a level of detailed understanding, the regulation of this transcription factor in the nucleus is still incomplete.…”

Section: Discussionmentioning

confidence: 99%

The intricate interplay between RNA viruses and NF-κB

Schmitz

Kracht

Saul

2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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RNA viruses have rapidly evolving genomes which often allow cross-species transmission and frequently generate new virus variants with altered pathogenic properties. Therefore infections by RNA viruses are a major threat to human health. The infected host cell detects trace amounts of viral RNA and the last years have revealed common principles in the biochemical mechanisms leading to signal amplification that is required for mounting of a powerful antiviral response. Components of the RNA sensing and signaling machinery such as RIG-I-like proteins, MAVS and the inflammasome inducibly form large oligomers or even fibers that exhibit hallmarks of prions. Following a nucleation event triggered by detection of viral RNA, these energetically favorable and irreversible polymerization events trigger signaling cascades leading to the induction of antiviral and inflammatory responses, mediated by interferon and NF-κB pathways. Viruses have evolved sophisticated strategies to manipulate these host cell signaling pathways in order to ensure their replication. We will discuss at the examples of influenza and HTLV-1 viruses how a fascinating diversity of biochemical mechanisms is employed by viral proteins to control the NF-κB pathway at all levels.

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HSP90 Protects the Human T-Cell Leukemia Virus Type 1 (HTLV-1) Tax Oncoprotein from Proteasomal Degradation To Support NF-κB Activation and HTLV-1 Replication

Cited by 38 publications

References 70 publications

Localization of MRP‐1 to the outer mitochondrial membrane by the chaperone protein HSP90β

Localization of MRP‐1 to the outer mitochondrial membrane by the chaperone protein HSP90β

Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes

The intricate interplay between RNA viruses and NF-κB

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