Stability of HTLV-2 antisense protein is controlled by PML nuclear bodies in a SUMO-dependent manner

Dubuisson, Louise; Lormières, Florence; Fochi, Stefania; Turpin, Jocelyn; Pasquier, Amandine; Douceron, Estelle; Oliva, Anaïs; Bazarbachi, Ali; Lallemand-Breitenbach, Valérie; Thé, Hugues de; Journo, Chloé; Mahieux, Renaud

doi:10.1038/s41388-018-0163-x

Cited by 13 publications

(13 citation statements)

References 37 publications

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“…Similar to HBZ, APH-2 inhibited Tax-2-induced NF-κB activity, but unexpectedly and unlike Tax-1, high expression of Tax-2 did not restore the activation of NF-κB (Figure 2B). Of note, this inhibitory effect of APH-2 was evident despite the fact that APH-2 was less expressed than HBZ in transfected cells, as previously reported (Panfil et al, 2016; Dubuisson et al, 2018). Because APH-2 appeared to be more potent than HBZ in the inhibition of Tax-mediated NF-κB activation, the effect of HBZ and APH-2 expression on the NF-κB promoter activation mediated by p65 over-expression was then compared in HEK293T cells.…”

Section: Resultssupporting

confidence: 83%

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TRAF3 Is Required for NF-κB Pathway Activation Mediated by HTLV Tax Proteins

et al. 2019

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Human T-cell leukemia viruses type 1 (HTLV-1) and type 2 (HTLV-2) share a common genome organization and expression strategy but have distinct pathological properties. HTLV-1 is the etiological agent of Adult T-cell Leukemia (ATL) and of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), whereas HTLV-2 does not cause hematological disorders and is only sporadically associated with cases of subacute myelopathy. Both HTLV genomes encode two regulatory proteins that play a pivotal role in pathogenesis: the transactivating Tax-1 and Tax-2 proteins and the antisense proteins HBZ and APH-2, respectively. We recently reported that Tax-1 and Tax-2 form complexes with the TNF-receptor associated factor 3, TRAF3, a negative regulator of the non-canonical NF-κB pathway. The NF-κB pathway is constitutively activated by the Tax proteins, whereas it is inhibited by HBZ and APH-2. The antagonistic effects of Tax and antisense proteins on NF-κB activation have not yet been fully clarified. Here, we investigated the effect of TRAF3 interaction with HTLV regulatory proteins and in particular its consequence on the subcellular distribution of the effector p65/RelA protein. We demonstrated that Tax-1 and Tax-2 efficiency on NF-κB activation is impaired in TRAF3 deficient cells obtained by CRISPR/Cas9 editing. We also found that APH-2 is more effective than HBZ in preventing Tax-dependent NF-κB activation. We further observed that TRAF3 co-localizes with Tax-2 and APH-2 in cytoplasmic complexes together with NF-κB essential modulator NEMO and TAB2, differently from HBZ and TRAF3. These results contribute to untangle the mechanism of NF-κB inhibition by HBZ and APH-2, highlighting the different role of the HTLV-1 and HTLV-2 regulatory proteins in the NF-κB activation.

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Section: Resultssupporting

confidence: 83%

“…pEF-p52 was kindly provided by Dr. Matsuoka. pcDNA3-VSV-APH-2, pSG5M-Tax2-His, His-HBZ have been previously described (Journo et al, 2013; Dubuisson et al, 2018). pSpCas9(BB)-2A-Puro (PX459) V2.0 vector was purchased from Addgene.…”

Section: Methodsmentioning

confidence: 99%

TRAF3 Is Required for NF-κB Pathway Activation Mediated by HTLV Tax Proteins

et al. 2019

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“…This conclusion was supported by our data showing that bafilomycin, a lysosomal inhibitor, also stabilized APH-2 expression. Although lysosomal degradation of APH-2 has not been reported previously, APH-2 has been shown to be degraded by the proteasome following its SUMOylation (45). Overall, our data support the view that, in addition to the proteasome, APH-2 is degraded by the lysosomal pathway.…”

Section: Discussionsupporting

confidence: 86%

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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“…We also found that APH-2 is more effective than HBZ in inhibiting NF-κB activation by Tax, and we proposed a model in which the recruitment of APH-2 in cytoplasmic structures with NF-κB factors may inhibit p65's nuclear translocation, leading to NF-κB inhibition [105]. Another property of APH-2 that distinguishes it from HBZ is its targeting to PML nuclear bodies, which leads to proteasomal degradation of APH-2 in a SUMO-dependent manner [123].…”

Section: Deregulation Of Nf-κb Activation By Hbzmentioning

confidence: 99%

NF-κB and MicroRNA Deregulation Mediated by HTLV-1 Tax and HBZ

et al. 2019

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The risk of developing adult T-cell leukemia/lymphoma (ATLL) in individuals infected with human T-cell lymphotropic virus 1 (HTLV-1) is about 3–5%. The mechanisms by which the virus triggers this aggressive cancer are still an area of intensive investigation. The viral protein Tax-1, together with additional regulatory proteins, in particular HTLV-1 basic leucine zipper factor (HBZ), are recognized as relevant viral factors required for both viral replication and transformation of infected cells. Tax-1 deregulates several cellular pathways affecting the cell cycle, survival, and proliferation. The effects of Tax-1 on the NF-κB pathway have been thoroughly studied. Recent studies also revealed the impact of Tax-1 and HBZ on microRNA expression. In this review, we summarize the recent progress in understanding the contribution of HTLV-1 Tax- and HBZ-mediated deregulation of NF-κB and the microRNA regulatory network to HTLV-1 pathogenesis.

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Stability of HTLV-2 antisense protein is controlled by PML nuclear bodies in a SUMO-dependent manner

Cited by 13 publications

References 37 publications

TRAF3 Is Required for NF-κB Pathway Activation Mediated by HTLV Tax Proteins

TRAF3 Is Required for NF-κB Pathway Activation Mediated by HTLV Tax Proteins

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

NF-κB and MicroRNA Deregulation Mediated by HTLV-1 Tax and HBZ

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