Chromatin Tethering of Incoming Foamy Virus by the Structural Gag Protein

Tobaly-Tapiero, Joelle; Bittoun, Patricia; Lehmann-Che, Jacqueline; Delelis, Olivier; Giron, Marie-Lou; Thé, Hugues de; Saı̈b, Ali

doi:10.1111/j.1600-0854.2008.00792.x

Cited by 71 publications

(115 citation statements)

References 52 publications

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“…Prototype foamy virus (PFV) Gag has also been observed in the nuclear compartment (39,48,55). The mechanism is novel, since PFV Gag does not possess a functional NLS and does not translocate to the nucleus of interphase cells.…”

Section: Discussionmentioning

confidence: 99%

Feline Immunodeficiency Virus Gag Is a Nuclear Shuttling Protein

Kemler

Saenz

Poeschla

2012

J Virol

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Lentiviral genomic RNAs are encapsidated by the viral Gag protein during virion assembly. The intracellular location of the initial Gag-RNA interaction is unknown. We previously observed feline immunodeficiency virus (FIV) Gag accumulating at the nuclear envelope during live-cell imaging, which suggested that trafficking of human immunodeficiency virus type 1 (HIV-1) and FIV Gag may differ. Here we analyzed the nucleocytoplasmic transport properties of both Gag proteins. We discovered that inhibition of the CRM1 nuclear export pathway with leptomycin B causes FIV Gag but not HIV-1 Gag to accumulate in the nucleus. Virtually all FIV Gag rapidly became intranuclear when the CRM1 export pathway was blocked, implying that most if not all FIV Gag normally undergoes nuclear cycling. In FIV-infected feline cells, some intranuclear Gag was detected in the steady state without leptomycin B treatment. When expressed individually, the FIV matrix (MA), capsid (CA), and nucleocapsid-p2 (NC-p2) domains were not capable of mediating leptomycin B-sensitive nuclear export of a fluorescent protein. In contrast, CA-NC-p2 did mediate nuclear export, with MA being dispensable. We conclude that HIV-1 and FIV Gag differ strikingly in a key intracellular trafficking property. FIV Gag is a nuclear shuttling protein that utilizes the CRM1 nuclear export pathway, while HIV-1 Gag is excluded from the nucleus. These findings expand the spectrum of lentiviral Gag behaviors and raise the possibility that FIV genome encapsidation may initiate in the nucleus.G ag is both necessary and sufficient for retrovirus particle formation and budding. The protein is translated on free polysomes and targeted to the plasma membrane, where virus particles are assembled (16). A central question is whether Gag and the viral genomic RNA (gRNA) associate at the plasma membrane or earlier during assembly and, if so, whether this occurs in the cytosol; in association with organelles, e.g., cotranslationally; or even in the nucleus, as was described previously for an alpharetrovirus (17). Human immunodeficiency virus type 1 (HIV-1) gRNAs become anchored at the plasma membrane before particle assembly is detectable, but it is not clear whether the Gag-gRNA complexes of this and other lentiviruses first form in the cytoplasm and then transit to the plasma membrane or the gRNA traffics there independently (26,27). Biochemical experiments supported the former scenario, with a monomer or low-order multimers forming on HIV-1 gRNAs and higher-order multimer formation depending on subsequent plasma membrane interactions (33).Gag is encoded by the full-length unspliced viral RNA. To circumvent the cellular checkpoint that prevents the export of intron-containing mRNA, lentiviruses express Rev, which functions as an adaptor between the cellular karyopherin CRM1/exportin-1 and a Rev response element (RRE) located in the 3= region of unspliced viral RNAs (9). However, the main cellular function of the CRM1 nuclear export pathway is the export of cellular proteins containing a...

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Section: Discussionmentioning

confidence: 99%

Feline Immunodeficiency Virus Gag Is a Nuclear Shuttling Protein

Kemler

Saenz

Poeschla

2012

J Virol

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“…1A) (23,24). To test if the GAGchromatin interaction is direct, we purified full-length hexahistidine (His 6 )-tagged PFV GAG protein and used recombinant mononucleosomes assembled from bacterially expressed human histones and 147-bp DNA with a strong positioning sequence (25).…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, prototype foamy virus (PFV), a member of the generally benign spumavirus retroviral genus, appears to be averse to generich regions and disfavors integration into genes (22). Encouraged by earlier observations that PFV GAG can bind chromatin (23,24), we determined a crystal structure of its chromatin-binding sequence (CBS) bound to a mononucleosome. We show that the CBS binds at the acidic patch in the surface of H2A-H2B heterodimer via an invariant conserved Arg anchor motif.…”

mentioning

confidence: 99%

Structural basis for spumavirus GAG tethering to chromatin

Lesbats

Serrao

Maskell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The interactions between a retrovirus and host cell chromatin that underlie integration and provirus expression are poorly understood. The prototype foamy virus (PFV) structural protein GAG associates with chromosomes via a chromatin-binding sequence (CBS) located within its C-terminal region. Here, we show that the PFV CBS is essential and sufficient for a direct interaction with nucleosomes and present a crystal structure of the CBS bound to a mononucleosome. The CBS interacts with the histone octamer, engaging the H2A-H2B acidic patch in a manner similar to other acidic patch-binding proteins such as herpesvirus latency-associated nuclear antigen (LANA). Substitutions of the invariant arginine anchor residue in GAG result in global redistribution of PFV and macaque simian foamy virus (SFV mac ) integration sites toward centromeres, dampening the resulting proviral expression without affecting the overall efficiency of integration. Our findings underscore the importance of retroviral structural proteins for integration site selection and the avoidance of genomic junkyards.retrovirus | integration | nucleosome | chromatin-binding

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“…Murine leukemia virus (MuLV) (p12) [133,134] Human immunodeficiency virus (HIV) (LEDGF/p75) [141] Avian sarcoma virus (ASV) (IN) [132] Foamy virus (FV) (Gag) [143,144] Epstein Barr virus (EBV) EBNA1 [147][148][149] Kaposi sarcoma-associated herpesvirus (KSHV) LANA [151,152,154] Bovine (BPV) and human papillomavirus (HPV) E2 [155][156][157][158] Simian vacuolating virus 40 (SV40) unknown [161,162] …”

Section: Viruses Chromatin Tethering Factormentioning

confidence: 99%

“…Recently, the FV group-specific antigen (Gag) was found to be the essential linker between the viral DNA in the PICs via its Cterminus and host chromosomes during mitosis through interaction with H2A/H2B histones via its Nterminus [143,144]. The substitution of this chromatin binding site with the chromatin binding site of LANA (see 6.2) allows binding of the incoming PICs onto host chromosomes but it does not restore full infectivity [143]. For ASV, the factors which translocate their PICs into the nucleus of (non)dividing cells are speculated or unknown e.g.…”

Section: Contrary To Mulvs Lentiviruses Such As Hiv-1 Infect Dividinmentioning

confidence: 99%