Novel interactions between the HTLV antisense proteins HBZ and APH-2 and the NFAR protein family: Implications for the HTLV lifecycles

Murphy, Jane; Hall, William W.; Ratner, Lee; Sheehy, Noreen

doi:10.1016/j.virol.2016.04.012

Cited by 11 publications

(12 citation statements)

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“…We observed that endogenous HRS localized in the cytoplasm in a granular pattern, which is consistent with previous reports. APH-2, as described previously, displays fluorescence in a speckle-like manner in the cytoplasm and the nucleus (8,16). In Fig.…”

Section: Resultsmentioning

confidence: 63%

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The ESCRT-0 Protein HRS Interacts with the Human T Cell Leukemia Virus Type 2 Antisense Protein APH-2 and Suppresses Viral Replication

Martini

Arone

Hasset

et al. 2019

J Virol

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The divergent clinical outcomes of human T cell leukemia virus type 1 (HTLV-1) and HTLV-2 infections have been attributed to functional differences in their antisense proteins. In contrast to HTLV-1 bZIP factor (HBZ), the role of the antisense protein of HTLV-2 (APH-2) in HTLV-2 infection is poorly understood. In previous studies, we identified the endosomal sorting complex required for transport 0 (ESCRT-0) subunit HRS as a novel interaction partner of APH-2 but not HBZ. HRS is a master regulator of endosomal protein sorting for lysosomal degradation and is hijacked by many viruses to promote replication. However, no studies to date have shown a link between HTLVs and HRS. In this study, we sought to characterize the interaction between HRS and APH-2 and to investigate the impact of HRS on the life cycle of HTLV-2. We confirmed a direct specific interaction between APH-2 and HRS and showed that the CC2 domain of HRS and the N-terminal domain of APH-2 mediate their interaction. We demonstrated that HRS recruits APH-2 to early endosomes, possibly furnishing an entry route into the endosomal/lysosomal pathway. We demonstrated that inhibition of this pathway using either bafilomycin or HRS overexpression substantially extends the half-life of APH-2 and stabilizes Tax2B expression levels. We found that HRS enhances Tax2B-mediated long terminal repeat (LTR) activation, while depletion of HRS enhances HTLV-2 production and release, indicating that HRS may have a negative impact on HTLV-2 replication. Overall, our study provides important new insights into the role of the ESCRT-0 HRS protein, and by extension the ESCRT machinery and the endosomal/lysosomal pathway, in HTLV-2 infection. IMPORTANCE While APH-2 is the only viral protein consistently expressed in infected carriers, its role in HTLV-2 infection is poorly understood. In this study, we characterized the interaction between the ESCRT-0 component HRS and APH-2 and explored the role of HRS in HTLV-2 replication. HRS is a master regulator of protein sorting for lysosomal degradation, a feature that is manipulated by several viruses to promote replication. Unexpectedly, we found that HRS targets APH-2 and possibly Tax2B for lysosomal degradation and has an overall negative impact on HTLV-2 replication and release. The negative impact of interactions between HTLV-2 regulatory proteins and HRS, and by extension the ESCRT machinery, may represent an important strategy used by HTLV-2 to limit virus production and to promote persistence, features that may contribute to the limited pathogenic potential of this infection.

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Section: Resultsmentioning

confidence: 63%

“…This led to the conclusion that APH-2 may have a protective role in HTLV-2 infection and may contribute to the nonpathogenic nature of HTLV-2. To date, however, few studies have examined interactions between APH-2 and cellular factors (12,15,16).…”

mentioning

confidence: 99%

The ESCRT-0 Protein HRS Interacts with the Human T Cell Leukemia Virus Type 2 Antisense Protein APH-2 and Suppresses Viral Replication

Martini

Arone

Hasset

et al. 2019

J Virol

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“…Plasmid constructs. The expression plasmids encoding Flag-HBZ and HIS-Tax1 were previously described (52,53). Plasmids encoding Flag-IRF7 (wild type), Flag-IRF7 aa 1 to 283 (Flag-IRF7 1-283), Flag-IRF7 283-503, and Flag-IRF7 283-466, together with the luciferase reporter plasmids for IFN-␣ and IFN-␤, were gifts from Fanxiu Zhu, Florida State University (54).…”

Section: Figmentioning

confidence: 99%

Positive and Negative Regulation of Type I Interferons by the Human T Cell Leukemia Virus Antisense Protein HBZ

Narulla

Alsairi

Charmier

et al. 2017

J Virol

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The pathogenesis of human T cell leukemia virus type 1 (HTLV-1) is strongly linked to the viral regulatory proteins Tax1 and HBZ, whose opposing functions contribute to the clinical outcome of infection. Type I interferons alpha and beta (IFN-α and IFN-β) are key cytokines involved in innate immunity, and IFN-α, in combination with other antivirals, is extensively used in the treatment of HTLV-1 infection. The relationship between HTLV-1 and IFN signaling is unclear, and to date the effect of HBZ on this pathway has not been examined. Here we report that HBZ significantly enhances interferon regulatory factor 7 (IRF7)-induced IFN-α- and IFN-stimulated response element (ISRE) promoter activities and IFN-α production and can counteract the inhibitory effect of Tax1. In contrast to this, we show that HBZ and Tax1 cooperate to inhibit the induction of IFN-β and ISRE promoters by IRF3 and IFN-β production. In addition, we reveal that HBZ enhances ISRE activation by IFN-α. We further show that HBZ enhances IRF7 and suppresses IRF3 activation by TBK1 and IKKε. We demonstrate that HBZ has no effect on virus-induced nuclear accumulation of IRF3, suggesting that it may inhibit IRF3 activity at a transcriptional level. We show that HBZ physically interacts with IRF7 and IKKε but not with IRF3 or TBK1. Overall, our findings suggest that both HBZ and Tax1 are negative regulators of immediate early IFN-β innate immune responses, while HBZ but not Tax1 positively regulates the induction of IFN-α and downstream IFN-α signaling. Type I interferons are powerful antiviral cytokines and are used extensively in the treatment of HTLV-1-induced adult T cell leukemia (ATL). To date, the relationship between HTLV-1 and the IFN pathway is poorly understood, and studies so far have focused on Tax1. Our study is unique in that it examined the effect of HBZ, alone or in combination with Tax1, on type I IFN signaling. This is important because HBZ is frequently the only viral protein expressed in infected cells, particularly at later stages of infection. A better understanding of the how HBZ regulates IFN signaling may lead to the development of therapeutics that can modify such responses and improve the clinical outcome for infected individuals.

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“…Another potential mechanism for this difference was described by Murphy et al in 2016. HBZ and APH-2 were individually found to interact with NFAR; HBZ interaction with NFAR resulted in decreased Tax-mediated transactivation while APH-2 interaction with NFAR did not [99].…”

Section: Hbz and Aph-2mentioning

confidence: 99%

Comparative virology of HTLV-1 and HTLV-2

2019

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Human T cell leukemia virus type 1 (HTLV-1) was the first discovered human retrovirus and the etiologic agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. Shortly after the discovery of HTLV-1, human T-cell leukemia virus type 2 (HTLV-2) was isolated from a patient with hairy cell leukemia. Despite possession of similar structural features to HTLV-1, HTLV-2 has not been definitively associated with lymphoproliferative disease. Since their discovery, studies have been performed with the goal of highlighting the differences between HTLV-1 and HTLV-2. A better understanding of these differences will shed light on the specific pathogenic mechanisms of HTLV-1 and lead to novel therapeutic targets. This review will compare and contrast the two oldest human retroviruses with regards to epidemiology, genomic structure, gene products, and pathobiology.

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Novel interactions between the HTLV antisense proteins HBZ and APH-2 and the NFAR protein family: Implications for the HTLV lifecycles

Cited by 11 publications

References 91 publications

The ESCRT-0 Protein HRS Interacts with the Human T Cell Leukemia Virus Type 2 Antisense Protein APH-2 and Suppresses Viral Replication

The ESCRT-0 Protein HRS Interacts with the Human T Cell Leukemia Virus Type 2 Antisense Protein APH-2 and Suppresses Viral Replication

Positive and Negative Regulation of Type I Interferons by the Human T Cell Leukemia Virus Antisense Protein HBZ

Comparative virology of HTLV-1 and HTLV-2

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