Both the PPPY and PTAP Motifs Are Involved in Human T-Cell Leukemia Virus Type 1 Particle Release

Wang, Huating; Machesky, Nicholas; Mansky, Louis M.

doi:10.1128/jvi.78.3.1503-1512.2004

Cited by 50 publications

(66 citation statements)

References 49 publications

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“…In agreement with other studies that utilized mini-Gag constructs, we observed that the PPXY motif can greatly stimulate the release of mini-Gag particles, which is in marked contrast to its apparent inability to stimulate the release of full-length Gag (41) but consistent with results reported for HTLV, where the PPXY motif has been shown to greatly increase particle release (8,24,74). We also observed a positive correlation between the extent of Gag ubiquitination and particle release in the context of a mini-Gag construct carrying the late domains of HTLV and Ebola virus, as reported earlier (41,67).…”

Section: Discussionsupporting

confidence: 81%

Nonstructural Protein 3 of Bluetongue Virus Assists Virus Release by Recruiting ESCRT-I Protein Tsg101

Wirblich

Bhattacharya

Roy

2006

J Virol

117

126

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The release of Bluetongue virus (BTV) and other members of the Orbivirus genus from infected host cells occurs predominantly by cell lysis, and in some cases, by budding from the plasma membrane. Two nonstructural proteins, NS3 and NS3A, have been implicated in this process. Here we show that both proteins bind to human Tsg101 and its ortholog from Drosophila melanogaster with similar strengths in vitro. This interaction is mediated by a conserved PSAP motif in NS3 and appears to play a role in virus release. The depletion of Tsg101 with small interfering RNA inhibits the release of BTV and African horse sickness virus, a related orbivirus, from HeLa cells up to fivefold and threefold, respectively. Like most other viral proteins which recruit Tsg101, NS3 also harbors a PPXY late-domain motif that allows NS3 to bind NEDD4-like ubiquitin ligases in vitro. However, the late-domain motifs in NS3 do not function as effectively in facilitating the release of mini Gag virus-like particles from 293T cells as the late domains from human immunodeficiency virus type 1, human T-cell leukemia virus, and Ebola virus. A mutagenesis study showed that the arginine residue in the PPRY motif is responsible for the low activity of the NS3 late-domain motifs. Our data suggest that the BTV late-domain motifs either recruit an antagonist that interferes with budding or fail to recruit an agonist which is different from NEDD4.

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Section: Discussionsupporting

confidence: 81%

Nonstructural Protein 3 of Bluetongue Virus Assists Virus Release by Recruiting ESCRT-I Protein Tsg101

Wirblich

Bhattacharya

Roy

2006

J Virol

117

126

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“…In the context of both intact PFV and in a PFV-based vector system, mutation of each individual candidate L domain had no effect on levels of Gag protein synthesis, but resulted in a significant reduction in the yield of virus particles. Mutation of either the PSAP or PPPI domain reduced viral titer by 2.5-to 10-fold, an effect similar in magnitude to that observed upon mutation of the L domains of other retroviruses (5,15,16,45,47). L domains frequently occur in combination and bind separate cofactors.…”

Section: Discussionmentioning

confidence: 62%

Identification of Domains in Gag Important for Prototypic Foamy Virus Egress

Patton

Morris

Chung

et al. 2005

J Virol

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Sequence motifs (L domains) have been described in viral structural proteins. Mutations in these lead to a defect at a late stage in virus assembly and budding. For several viruses, recruitment of an endosomal sorting complexes required for transport 1 subunit (Tsg101), a component of the class E vacuolar protein sorting (EVPS) machinery, is a prerequisite for virion budding. To effect this, Tsg101 interacts with the PT/SAP L domain. We have identified candidate L-domain motifs, PSAP, PPPI, and YEIL, in the prototypic foamy virus (PFV) Gag protein, based on their homology to known viral L domains. Mutation of the PSAP and PPPI motifs individually reduced PFV egress, and their combined mutation had an additive effect. When PSAP was mutated, residual infectious PFV release was unaffected by dominant negative Vps4 (an ATPase involved in the final stages of budding), and sensitivity to dominant negative Tsg101 was dramatically reduced, suggesting that the PSAP motif functions as a conventional class E VPS-dependent L domain. Consistent with this notion, yeast two-hybrid analysis showed a PSAP motif-dependent interaction between PFV Gag and Tsg101. Surprisingly, PFV release which is dependent on the PPPI motif was Vps4-independent and was partially inhibited by dominant negative Tsg101, suggesting that PPPI functions by an unconventional mechanism to facilitate PFV egress. Mutation of the YEIL sequence completely abolished particle formation and also reduced the rate of Gag processing by the viral protease, suggesting that the integrity of YEIL is required at an assembly step prior to budding and YEIL is not acting as an L domain.

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“…In HTLV-1, there are two conserved late domain motifs, PPPY and PTAP that are found in the matrix region (161,188). Specifically, the late domains of HTLV-1 Gag have recently been found to recruit ubiquitin ligases Nedd4 and Tsg101, a protein of the ESCRT-1 complex, to facilitate the budding process (14).…”

Section: Gagmentioning

confidence: 99%

HTLV-1 Tax Effects on Cellular Mitotic Regulation

Merling¹

2007

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The human T-cell leukemia virus 1 (HTLV-1) encodes the tax gene (transactivator encoded by the pX region) which is a potent activator of viral transcription and Nuclear , this cyclin-dependent kinase inhibitor may also play a role in tax-IRS.As part of the research presented in this dissertation, a collection of HTLV-1 tax point mutants were isolated that permit normal growth of S. cerevisiae. Similar to wild-type tax, many mutants (C23W, A108T, L159F, and L235F) transactivated both the HTLV long terminal repeat (LTR) and the NF-!B reporters. The V19M mutant preferentially activated NF-!B, but was attenuated in LTR activation. None of the mutants significantly elevated the levels of p21 CIP1/WAF1 and p27 KIP1 , indicating that dramatic Tax-induced surges in p21and p27 KIP1 occurs by mechanisms distinct from NF-!B and LTR activation. Importantly, the ability of these mutants to activate APC was attenuated or abrogated. These data show that Tax-induced rapid senescence is causally associated with APC activation and suggest iv that the mitotic abnormalities that are associated with premature APC activation might play an important role in cell transformation by Tax.In a parallel study, we demonstrate that Tax interacts with both centrosomal Nek2-associated protein 1 (C-Nap1), a large coiled-coil protein that maintains centrosome cohesion, and protein phosphatase 1 (PP1) and that these interactions localize to the centrosome. Furthermore, in cells expressing tax, C-Nap1 phosphorylation is greatly diminished. C-Nap1 phosphorylation status plays an important role in centrosome cycle progression; PP1-mediated dephosphorylation of C-Nap1 maintains centriolar cohesion during interphase, and never in mitosis A (NIMA)-related kinase 2 (Nek2A)-mediated phosphorylation of C-Nap1 during G2/M triggers C-Nap1 dissociation from duplicated centrosomes permitting normal centrosome disjunction. Our data suggest that Tax, through recruitment of PP1 to C-Nap1, may permit prolonged C-Nap1 dephosphorylation thereby disrupting normal centrosome disjunction leading to observed Tax-induced centrosome abnormalities and distinct microtubule organizing center (MTOC) loss.Our studies have revealed two distinct pathways through which Tax could contribute to oncogenesis. First, our Tax mutants that retained LTR and NF-!B activation properties but were impaired in APC activation were also defective in the ability to transform Rat1 fibroblasts. Therefore, premature APC activation by Tax appears to correlate with the ability of Tax to induce cellular transformation. Second, our demonstration of Tax-mediated alterations in C-Nap1 phosphorylation cycle offers an explanation for the centrosome abnormalities and mitotic apparatus defects observed in response to Tax expression.Chromosomal abnormalities resulting from such mitotic apparatus defects may be expected to contribute to the oncogenic potential of Tax.v

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Both the PPPY and PTAP Motifs Are Involved in Human T-Cell Leukemia Virus Type 1 Particle Release

Cited by 50 publications

References 49 publications

Nonstructural Protein 3 of Bluetongue Virus Assists Virus Release by Recruiting ESCRT-I Protein Tsg101

Nonstructural Protein 3 of Bluetongue Virus Assists Virus Release by Recruiting ESCRT-I Protein Tsg101

Identification of Domains in Gag Important for Prototypic Foamy Virus Egress

HTLV-1 Tax Effects on Cellular Mitotic Regulation

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