Titration of cellular export factors, but not heteromultimerization, is the molecular mechanism of trans-dominant HTLV-1 Rex mutants

Heger, Peter; Rosorius, Olaf; Hauber, Joachim; Stauber, Roland H.

doi:10.1038/sj.onc.1202762

Cited by 34 publications

(37 citation statements)

References 81 publications

(73 reference statements)

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“…4C). Our results contradict a previous paper suggesting that p21Rex may inhibit p27Rex (24). In that study, the authors used a 4-to 10-fold excess of a p21RexGFP expression vector in order to see an effect on p27Rex-mediated export.…”

Section: Resultscontrasting

confidence: 56%

Nuclear Export and Expression of Human T-Cell Leukemia Virus Type 1 tax / rex mRNA Are RxRE/Rex Dependent

Bai

Sinha-Datta

et al. 2012

J Virol

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Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus associated with the lymphoproliferative disease adult Tcell leukemia/lymphoma (ATL) and the neurodegenerative disorder tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). Replication of HTLV-1 is under the control of two major trans-acting proteins, Tax and Rex. Previous studies suggested that Tax activates transcription from the viral long terminal repeat (LTR) through recruitment of cellular CREB and transcriptional coactivators. Other studies reported that Rex acts posttranscriptionally and allows the cytoplasmic export of unspliced or incompletely spliced viral mRNAs carrying gag/pol and env only. As opposed to HIV's Rev-responsive element (RRE), the Rex-responsive element (RxRE) is present in all viral mRNAs in HTLV-1. However, based on indirect observations, it is believed that nuclear export and expression of the doubly spliced tax/rex RNA are Rex independent. In this study, we demonstrate that Rex does stimulate Tax expression, through nuclear-cytoplasmic export of the tax/rex RNA, even though a Rex-independent basal export mechanism exists. This effect was dependent upon the RxRE element and the RNA-binding activity of Rex. In addition, Rex-mediated export of tax/rex RNA was CRM1 dependent and inhibited by leptomycin B treatment. Like all other retroviruses, human T-cell leukemia virus type 1 (HTLV-1) has limited genetic information restricted by the small size of its genome. To overcome its small genome while reducing its dependency on the host cell machinery, HTLV-1 has evolved many strategies, including ribosome frameshifts, overlapping reading frames, complex alternative splicing patterns, reverse-sense RNA transcripts, and posttranslational processing/ modifications of viral proteins which ascribe distinct functions to them. Early observations of the existence of three major viral RNAs expressed in HTLV-1-infected cells, i.e., gag/pol, env, and tax/rex RNAs, led to the hypothesis that Rex positively regulates gag/pol and env RNAs while concomitantly reducing the abundance of the tax/rex RNA (25). Hence, HTLV-1 replication has been thought to be regulated by Tax and Rex proteins (14,27), though evidence suggests that additional viral proteins may also play an important role during the virus replication cycle (5, 32).Tax interaction with CREB family members and coactivators (CBP, P300, and PCAF) results in a high-molecular-weight complex with high affinity for binding to and transactivating the viral long terminal repeat (LTR) (15,23,26,30). Rex has at least three domains that are important for its functions: an arginine-rich region important for binding to the Rex-responsive element (RxRE) (8); a region required for multimerization of Rex, a step required for assembly onto the RxRE (6, 9); and a leucine-rich nuclear export signal that interacts with the nuclear export receptor, CRM1 (17,19). The ability of Rex to regulate expression of the gag and env structural genes posttranscriptionally is rigorously dependent o...

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Section: Resultscontrasting

confidence: 56%

Nuclear Export and Expression of Human T-Cell Leukemia Virus Type 1 tax / rex mRNA Are RxRE/Rex Dependent

Bai

Sinha-Datta

et al. 2012

J Virol

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“…3A). The low level of fluorescence of RemGFP was also absent from the nucleoli, which is typical of GFPRem and other Rev-like proteins (21,37,43) (see Fig. 3B) and reminiscent of the behavior of Rem cleavage site mutants (7).…”

Section: Discussionmentioning

confidence: 95%

Requirements for Mouse Mammary Tumor Virus Rem Signal Peptide Processing and Function

Byun

Halani

Gou

et al. 2012

J Virol

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“…The same localization and tra cking pattern was observed in the p53 negative cell line H1299 (e,f) or the p53 and Mdm2 negative cell line X174 (g,h). The presence of p21Rex-BFP in the same cell was veri®ed using the appropriate ®lter to detect BFP and mediated by the CRM1 export pathway (Fornerod et al, 1997;Heger et al, 1999;Stauber et al, 1998a). To understand how adenoviral or retroviral shuttle proteins exploit this export pathway, we reasoned that a shuttle protein with a high a nity for common export factors should be able to a ect the tra cking of a shuttle protein with a lower a nity in trans.…”

Section: Retroviral Shuttle Proteins Are Not Affected By E1b Traffickmentioning

confidence: 99%

The adenovirus type 5 E1B-55K oncoprotein is a highly active shuttle protein and shuttling is independent of E4orf6, p53 and Mdm2

et al. 2000

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The E1B-55K and E4orf6 oncoproteins of adenovirus type 5 are involved in the export of viral mRNAs. Previously, it was suggested that a complex composed of E1B-55K and E4orf6 serves as a nucleocytoplasmic transporter for viral mRNAs in which the E4orf6 protein directs both nuclear import and export. We now demonstrate that the E1B-55K protein itself shuttles e ciently in the absence of E4orf6. In addition, E1B-55K tra cking was independent of the de®ned shuttle proteins Mdm2 or p53, which interacts with E1B-55K. The identi®ed N-terminal E1B-55K leucine-rich nuclearexport signal (NES) conferred rapid nuclear export even in a heterologous system in contrast to the postulated E4orf6NES. Interestingly, although shuttling was blocked by inhibitors of the CRM1 mediated export pathway, E1B-55K inhibited neither the activity nor the tra cking of the retroviral shuttle proteins HIV-1 Rev and HTLV-1 Rex. In contrast, Rev or Rex blocked the nuclear export of E1B-55K, most likely by competing for essential export factors. Our results provide new insights into the regulation of the adenovirus mRNA export system and the processes of adenovirus mediated transformation. Oncogene (2000) 19, 850 ± 857.

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Titration of cellular export factors, but not heteromultimerization, is the molecular mechanism of trans-dominant HTLV-1 Rex mutants

Cited by 34 publications

References 81 publications

Nuclear Export and Expression of Human T-Cell Leukemia Virus Type 1 tax / rex mRNA Are RxRE/Rex Dependent

Nuclear Export and Expression of Human T-Cell Leukemia Virus Type 1 tax / rex mRNA Are RxRE/Rex Dependent

Requirements for Mouse Mammary Tumor Virus Rem Signal Peptide Processing and Function

The adenovirus type 5 E1B-55K oncoprotein is a highly active shuttle protein and shuttling is independent of E4orf6, p53 and Mdm2

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