Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

Stavrou, Spyridon; Nitta, Takayuki; Kotla, Swathi; Ha, Dat P.; Nagashima, Kunio; Rein, Alan; Fan, Hung; Ross, Susan R.

doi:10.1073/pnas.1217399110

Cited by 84 publications

(208 citation statements)

References 54 publications

(74 reference statements)

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“…NSG mice lack cells of the adaptive immune system (B-, T-and NK-cells) and have several defects in classic innate functions, including an absent hemolytic complement system, reduced dendritic cell function, and defective macrophage activity (10). Our study also demonstrated that E-MuLV replication is not blocked by the Fv1 restriction factor, which is the most common and powerful restriction against MuLV in the murine system at the intracellular level (18); nor has the Emv30 provirus been subject to incapacitating mutations, reflecting its relatively new insertion into the NOD germ line and the low impact of APOCBEC3 restriction on this class of MuLVs (29). Thus, NOD mice differ strikingly from the common inbred mouse strains DBA/2, BALB/c, and B6, in which the eERV provirus is replication incompetent, restricted by the Fv1 factor, or both, respectively.…”

Section: Discussionmentioning

confidence: 71%

Endogenous retrovirus induces leukemia in a xenograft mouse model for primary myelofibrosis

Triviai

Ziegler

Bergholz

et al. 2014

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

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Significance Immunodeficient mice are important tools to define stem cells that drive malignancies (cancers). Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm that can progress to malignant leukemia. In a study to define PMF stem cells in transplanted mice, we observed a high incidence of mouse leukemia. We show that endogenous retrovirus (ERV), whose replication is unrestricted in immunodeficient mice, are pathogenic in the PMF-xenograft microenvironment, likely because of increased numbers of proliferating mouse cells stimulated by PMF-derived cells. Proliferating cells are targets of retroviral transformation and spontaneous mutations, and thus susceptible to leukemia induction. These results substantiate the importance of paracrine mechanisms in PMF disease and expose the presence of replicating ERVs in mice commonly used to model human diseases.

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Section: Discussionmentioning

confidence: 71%

Endogenous retrovirus induces leukemia in a xenograft mouse model for primary myelofibrosis

Triviai

Ziegler

Bergholz

et al. 2014

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

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“…In contrast, perhaps the structure of MLV particles limits the interconversion of these hypothetical forms of mA3. Recent evidence indicates that the glyco-Gag of MLV affects virus structure in a way that interferes with mA3 action (43,44). In any case, further work will be required to elucidate the mechanisms of mA3 restriction of MLV and of the resistance of MLV to mA3-induced hypermutation.…”

Section: Figmentioning

confidence: 99%

Biochemical and Biological Studies of Mouse APOBEC3

Nair

Sánchez-Martínez

et al. 2014

J Virol

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Many murine leukemia viruses (MLVs) are partially resistant to restriction by mouse APOBEC3 (mA3) and essentially fully resistant to induction of G-to-A mutations by mA3. In contrast, Vif-deficient HIV-1 (⌬Vif HIV-1) is profoundly restricted by mA3, and the restriction includes high levels of G-to-A mutation. Human APOBEC3G (hA3G), unlike mA3, is fully active against MLVs. We produced a glutathione S-transferase-mA3 fusion protein in insect cells and demonstrated that it possesses cytidine deaminase activity, as expected. This activity is localized within the N-terminal domain of this 2-domain protein; the C-terminal domain is enzymatically inactive but required for mA3 encapsidation into retrovirus particles. We found that a specific arginine residue and several aromatic residues, as well as the zinc-coordinating cysteines in the C-terminal domain, are necessary for mA3 packaging; a structural model of this domain suggests that these residues line a potential nucleic acid-binding interface. Mutation of a few potential phosphorylation sites in mA3 drastically reduces its antiviral activity by impairing either deaminase activity or its encapsidation. mA3 deaminates short single-stranded DNA oligonucleotides preferentially toward their 3= ends, whereas hA3G exhibits the opposite polarity. However, when packaged into infectious ⌬Vif HIV-1 virions, both mA3 and hA3G preferentially induce deaminations toward the 5= end of minus-strand viral DNA, presumably because of the sequence of events during reverse transcription in vivo. Despite the fact that mA3 in MLV particles does not induce detectable deaminations upon infection, its deaminase activity is easily detected in virus lysates. We still do not understand how MLV resists mA3-induced G-to-A mutation. IMPORTANCEOne way that mammalian cells defend themselves against infection by retroviruses is with APOBEC3 proteins. These proteins convert cytidine bases to uridine bases in retroviral DNA. However, mouse APOBEC3 protein blocks infection by murine leukemia viruses without catalyzing this base change, and the mechanism of inhibition is not understood in this case. We have produced recombinant mouse APOBEC3 protein for the first time and characterized it here in a number of ways. Our mutational studies shed light on the mechanism by which mouse APOBEC3 protein is incorporated into retrovirus particles. While mouse APOBEC3 does not catalyze base changes in murine leukemia virus DNA, it can be recovered from these virus particles in enzymatically active form; it is still not clear why it fails to induce base changes when these viruses infect new cells. M ammals possess several innate mechanisms for defense against retroviruses. One of these restriction factors is the APOBEC3 system. APOBEC3 proteins are cytidine deaminases (1). In many cases, they are encapsidated into assembling virions; when these virions infect a new cell and copy their RNA into DNA, the APOBEC3 protein from the virion binds to the singlestranded DNA (ssDNA; the initial DNA product) and deamin...

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“…However, M-MLV becomes much more sensitive to restriction by mA3 when expression of the glycosylated viral Pr80 Gag (gPr80) protein is suppressed (15,18). This is reportedly caused by gPr80 blocking access of mA3 to the reverse transcription complex in viral cores (15).…”

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confidence: 99%

“…The most striking example is the Moloney MLV (M-MLV) gammaretrovirus, which is modestly restricted by mA3 in the absence of detectable G-to-A hypermutation, despite efficiently packaging mA3 into virions (33,(36)(37)(38)(39)(40). However, M-MLV becomes much more sensitive to restriction by mA3 when expression of the glycosylated viral Pr80 Gag (gPr80) protein is suppressed (15,18). This is reportedly caused by gPr80 blocking access of mA3 to the reverse transcription complex in viral cores (15).…”

mentioning

confidence: 99%

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N -Linked Glycosylation Protects Gammaretroviruses against Deamination by APOBEC3 Proteins

Gerpe

Renner

Bélanger

et al. 2015

J Virol

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Retroviruses are pathogens with rapid infection cycles that can be a source of disease, genome instability, and tumor development in their hosts. Host intrinsic restriction factors, such as APOBEC3 (A3) proteins, are constitutively expressed and dedicated to interfering with the replication cycle of retroviruses. To survive, propagate, and persist, retroviruses must counteract these restriction factors, often by way of virus genome-encoded accessory proteins. Glycosylated Gag, also called glycosylated Pr80 Gag (gPr80), is a gammaretrovirus genome-encoded protein that inhibits the antiretroviral activity of mouse A3 (mA3). Here we show that gPr80 exerts two distinct inhibitory effects on mA3: one that antagonizes deamination-independent restriction and another one that inhibits its deaminase activity. More specifically, we find that the number of N-glycosylated residues in gPr80 inversely correlates with the sensitivity of a gammaretrovirus to deamination by mouse A3 and also, surprisingly, by human A3G. Finally, our work highlights that retroviruses which have successfully integrated into the mouse germ line generally express a gPr80 with fewer glycosylated sites than exogenous retroviruses. This observation supports the suggestion that modulation of A3 deamination intensity could be a desirable attribute for retroviruses to increase genetic diversification and avoid immune detection. Overall, we present here the first description of how gammaretroviruses employ posttranslational modification to antagonize and modulate the activity of a host genome-encoded retroviral restriction factor. IMPORTANCEAPOBEC3 proteins are host factors that have a major role in protecting humans and other mammals against retroviruses. These enzymes hinder their replication and intensely mutate their DNA, thereby inactivating viral progeny and the spread of infection. Here we describe a newly recognized way in which some retroviruses protect themselves against the mutator activity of APOBEC3 proteins. We show that gammaretroviruses expressing an accessory protein called glycosylated Gag, or gPr80, use the host's posttranslational machinery and, more specifically, N-linked glycosylation as a way to modulate their sensitivity to mutations by APOBEC3 proteins. By carefully controlling the amount of mutations caused by APOBEC3 proteins, gammaretroviruses can find a balance that helps them evolve and persist.

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Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

Cited by 84 publications

References 54 publications

Endogenous retrovirus induces leukemia in a xenograft mouse model for primary myelofibrosis

Endogenous retrovirus induces leukemia in a xenograft mouse model for primary myelofibrosis

Biochemical and Biological Studies of Mouse APOBEC3

N -Linked Glycosylation Protects Gammaretroviruses against Deamination by APOBEC3 Proteins

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