The HTLV-1 oncoprotein Tax is modified by the ubiquitin related modifier 1 (Urm1)

Abstract

BackgroundAdult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy secondary to chronic human T-cell lymphotropic virus 1 infection, triggered by the virally encoded oncoprotein Tax. The transforming activity and subcellular localization of Tax is strongly influenced by posttranslational modifications, among which ubiquitylation and SUMOylation have been identified as key regulators of the nuclear/cytoplasmic shuttling of Tax, as well as its ability to activate NF-κB signaling.ResultsAdding to the complex posttranslational modification landscape of Tax, we here demonstrate that Tax also interacts with the ubiquitin-related modifier 1 (Urm1). Conjugation of Urm1 to Tax results in a redistribution of Tax to the cytoplasm and major increase in the transcription of the NF-ĸB targets Rantes and interleukin-6. Utilizing a tax-transgenic Drosophila model, we show that the Urm1-dependent subcellular targeting of Tax is evolutionary conserved, and that the presence of Urm1 is strongly correlated with the transcriptional output of Diptericin, an antimicrobial peptide and established downstream target of NF-κB in flies.ConclusionsThese data put forward Urm1 as a novel Tax modifier that modulates its oncogenic activity and hence represents a potential novel target for developing new strategies for treating ATL.

Drosophila as a Model for Infectious Diseases

“…Further work in cultured human T cells also demonstrated that Tax1, but not Tax2, induces expression of OX40L, a tumor necrosis factor ligand, by binding to an IKK [ 63 ]. This and additional studies corroborate to show NF-κB signaling becomes misregulated when Tax1 is over-expressed [ 58 ], demonstrating how data from Drosophila can facilitate the understanding of why related viruses can cause different diseases in humans.…”

“…These modifications are considered to alter the activity, turnover, and subcellular localization of Tax1 [ 57 ]. Work in Drosophila combined with human cell-based assays identified a novel posttranslational modification on Tax1 and demonstrated the in vivo significance of this alteration [ 58 ]. In this study, Hleihel et al first showed that Tax1 could undergo Urmylation, a process in which Urm1 (Ubiquitin-related modifier 1), a ubiquitin-like protein, is covalently conjugated to the target protein [ 59 ] ( Figure 1 ).…”

Epstein–Barr Virus DNA Exacerbates Colitis Symptoms in a Mouse Model of Inflammatory Bowel Disease

“…RNA was extracted [ 23 , 24 , 25 , 26 ] from colon tissues using Qiazol (Qiagen, Hilden, Germany) as per manufacturer recommendations. For this purpose, 1 mL of the Qiazol reagent was added to 100 mg of mouse colon tissue and the sample was then homogenized using a Biospec Tissue Tearor (Bartlesville, OK).…”

Urm1: A Non-Canonical UBL

“…According to this report, Urm1 is conjugated to the viral oncoprotein Tax in human and fly models, leading to Tax redistribution to the cytosol thereby promoting adult T-cell leukemia (ATL). Interestingly, the localization of Tax is also controlled by ubiquitin and SUMO [ 106 ].…”