The SUMO-targeted ubiquitin ligase RNF4 regulates localization and function of the HTLV-1 oncoprotein Tax

Fryrear, Kimberly A.; Kerscher, Oliver; Semmes, O. John

doi:10.1186/1742-4690-8-s1-a126

Cited by 11 publications

(10 citation statements)

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“…The requirement of STAMBPL1 for Tax nuclear export is readily observed when cells are exposed to UV light. A recent study has demonstrated that the SUMO-targeted E3 ubiquitin ligase RNF4 also regulates Tax trafficking and nuclear export in response to genotoxic stress (9). However, RNF4 directly ubiquitinates Tax to trigger its nuclear export.…”

Section: Discussionmentioning

confidence: 99%

An RNA Interference Screen Identifies the Deubiquitinase STAMBPL1 as a Critical Regulator of Human T-Cell Leukemia Virus Type 1 Tax Nuclear Export and NF-κB Activation

Lavorgna

Harhaj

2012

J Virol

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The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein actively shuttles between the nucleus, where it interacts with transcriptional and splicing regulatory proteins, and the cytoplasm, where it activates NF-κB. Posttranslational modifications of Tax such as ubiquitination regulate its subcellular localization and hence its function; however, the regulation of Tax trafficking and NF-κB activation by host factors is poorly understood. By screening a deubiquitinating (DUB) enzyme small interfering RNA (siRNA) library, we identified the metalloprotease STAM-binding protein-like 1 (STAMBPL1) as a positive regulator of Tax-mediated NF-κB activation. Overexpression of wild-type STAMBPL1, but not a catalytically inactive mutant, enhanced Tax-mediated NF-κB activation, whereas silencing of STAMBPL1 with siRNA impaired Tax activation of both the canonical and noncanonical NF-κB signaling pathways. STAMBPL1 regulated Tax-induced NF-κB signaling indirectly by controlling Tax nuclear/cytoplasmic transport and was required for DNA damage-induced Tax nuclear export. Together, these results reveal that the deubiquitinase STAMBPL1 is a key regulator of Tax trafficking and function.

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Section: Discussionmentioning

confidence: 99%

An RNA Interference Screen Identifies the Deubiquitinase STAMBPL1 as a Critical Regulator of Human T-Cell Leukemia Virus Type 1 Tax Nuclear Export and NF-κB Activation

Lavorgna

Harhaj

2012

J Virol

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“…27 Using PLA, we indeed observed both in HuT-102 and C91PL cells, a basal nuclear RNF4 interaction with Tax ( Figure 4A; supplemental Figure 3D). On AS/IFN exposure, the interaction signals became predominantly cytoplasmic ( Figure 4A; supplemental Figure 3D).…”

Section: Rnf4 Ubiquitinates Poly-sumoylated Taxmentioning

confidence: 88%

ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation

Dassouki

Şahin

Hajj

et al. 2015

Blood

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Key Points• Survival of ATL cells depends on continuous Tax expression.• Arsenic/interferon combination induces SUMO/PML/RNF4-mediated Tax degradation.The human T-cell lymphotropic virus type I (HTLV-1) Tax transactivator initiates transformation in adult T-cell leukemia/lymphoma (ATL), a highly aggressive chemotherapyresistant malignancy. The arsenic/interferon combination, which triggers degradation of the Tax oncoprotein, selectively induces apoptosis of ATL cell lines and has significant clinical activity in Tax-driven murine ATL or human patients. However, the role of Tax loss in ATL response is disputed, and the molecular mechanisms driving degradation remain elusive. Here we demonstrate that ATL-derived or HTLV-1-transformed cells are dependent on continuous Tax expression, suggesting that Tax degradation underlies clinical responses to the arsenic/ interferon combination. The latter enforces promyelocytic leukemia protein (PML) nuclear body (NB) formation and partner protein recruitment. In arsenic/interferon-treated HTLV-1 transformed or ATL cells, Tax is recruited onto NBs and undergoes PML-dependent hypersumoylation by small ubiquitin-like modifier (SUMO)2/3 but not SUMO1, ubiquitination by RNF4, and proteasome-dependent degradation. Thus, the arsenic/interferon combination clears ATL through degradation of its Tax driver, and this regimen could have broader therapeutic value by promoting degradation of other pathogenic sumoylated proteins. (Blood. 2015;125(3):474-482)

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“…40 Our SILAC screen uncovered MDC1 and 53BP1 as IR-induced SUMO-2 target proteins. These proteins could also be involved in the early phase of RNF4 recruitment to sites of DNA damage.…”

Section: Discussionmentioning

confidence: 99%

RNF4 is required for DNA double-strand break repair in vivo

et al. 2012

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Unrepaired DNA double-strand breaks (DSBs) cause genetic instability that leads to malignant transformation or cell death. Cells respond to DSBs with the ordered recruitment of signaling and repair proteins to the sites of DNA lesions. Coordinated protein SUMOylation and ubiquitylation have crucial roles in regulating the dynamic assembly of protein complexes at these sites. However, how SUMOylation influences protein ubiquitylation at DSBs is poorly understood. We show herein that Rnf4, an E3 ubiquitin ligase that targets SUMO-modified proteins, accumulates in DSB repair foci and is required for both homologous recombination (HR) and non-homologous end joining repair. To establish a link between Rnf4 and the DNA damage response (DDR) in vivo, we generated an Rnf4 allelic series in mice. We show that Rnf4-deficiency causes persistent ionizing radiationinduced DNA damage and signaling, and that Rnf4-deficient cells and mice exhibit increased sensitivity to genotoxic stress. Mechanistically, we show that Rnf4 targets SUMOylated MDC1 and SUMOylated BRCA1, and is required for the loading of Rad51, an enzyme required for HR repair, onto sites of DNA damage. Similarly to inactivating mutations in other key regulators of HR repair, Rnf4 deficiency leads to age-dependent impairment in spermatogenesis. These findings identify Rnf4 as a critical component of the DDR in vivo and support the possibility that Rnf4 controls protein localization at DNA damage sites by integrating SUMOylation and ubiquitylation events.

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The SUMO-targeted ubiquitin ligase RNF4 regulates localization and function of the HTLV-1 oncoprotein Tax

Cited by 11 publications

References 0 publications

An RNA Interference Screen Identifies the Deubiquitinase STAMBPL1 as a Critical Regulator of Human T-Cell Leukemia Virus Type 1 Tax Nuclear Export and NF-κB Activation

An RNA Interference Screen Identifies the Deubiquitinase STAMBPL1 as a Critical Regulator of Human T-Cell Leukemia Virus Type 1 Tax Nuclear Export and NF-κB Activation

ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation

RNF4 is required for DNA double-strand break repair in vivo

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