The retroviral accessory proteins S2, Nef, and glycoMA use similar mechanisms for antagonizing the host restriction factor SERINC5

Ahmad, Iqbal; Li, Sunan; Li, Rongrong; Chai, Qingqing; Zhang, Lixin; Wang, Bin; Yu, Changqing; Zheng, Yong Hui

doi:10.1074/jbc.ra119.007662

Cited by 29 publications

(38 citation statements)

References 29 publications

(50 reference statements)

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“…In order to elucidate the Ser5 antiviral mechanism, we adopted a bimolecular fluorescence complementation (BiFC) assay to detect Env-Env association in live cells (24). We previously detected the specific Nef-Ser5, glycoGag-Ser5, and S2-Ser5 interactions using this assay (8)(9)(10). A hemagglutinin (HA)-tagged VN or FLAG-tagged VC gene fragment was linked to the last codon of NL and AD8 gp160, and these new gene fragments were inserted into a proviral vector, pH22, by replacing the entire gp160 and 5= portion of nef ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to Nef, Ser5 is antagonized by murine leukemia virus (MLV) glycosylated Gag (glycoGag) (2,3) and equine infectious anemia virus (EIAV) S2 proteins (6,7). We recently reported that Nef, glycoGag, and S2 proteins all target Ser5 to the endosome/lysosome pathways for degradation (8)(9)(10). Thus, Ser5 is an important restriction factor for a wide range of retroviruses.…”

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confidence: 99%

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CD4 Expression and Env Conformation Are Critical for HIV-1 Restriction by SERINC5

Zhang

Shi

Qiu

et al. 2019

J Virol

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Serine incorporator 5 (SERINC5) is a recently identified restriction factor that strongly blocks HIV-1 entry but is counteracted by Nef. Notably, tier 1 HIV-1 Env proteins are sensitive to SERINC5, whereas the majority of tier 2/3 Env proteins are resistant to SERINC5, when viruses are produced from CD4-negative cells and tested by a single-round replication assay. Here, we investigated the Env-dependent SERINC5 antiviral mechanism by comparing tier 1 NL Env with tier 3 AD8 Env proteins. We found that when NL and AD8 viruses were inoculated into CD4+ T cells and human peripheral blood mononuclear cells (PBMCs), the propagation of the two viruses was restricted to a similar level when Nef was not expressed. Using a bimolecular fluorescence complementation (BiFC) assay, we detected Env-Env association and Env-SERINC5 interactions. A much greater level of NL Env-SERINC5 interactions was detected than was AD8 Env-SERINC5 interactions, which was further validated by immunoprecipitation assays. In addition, SERINC5 dissociated the NL Env trimeric complex more effectively than the AD8 Env trimeric complex when CD4 was not expressed. However, when CD4 was expressed, SERINC5 became more capable of interacting with AD8 Env and dissociating its trimeric complex. Moreover, AD8 and several other tier 2/3 viruses produced in the presence of CD4 became sensitive to SERINC5 when measured by the single-round replication assay. Because tier 1 and tier 2/3 Env trimers have open and closed conformations, respectively, and CD4 opens the closed conformation, we conclude that SERINC5 selectively dissociates Env trimers with an open conformation to restrict HIV-1 replication. IMPORTANCE Restriction factors provide the first line of defense against retrovirus infection by posing several blocks to the viral replication cycle. SERINC5 is a novel restriction factor that strongly blocks HIV-1 entry, although it is counteracted by Nef. Currently, it is still unclear how HIV-1 entry is blocked by SERINC5. Notably, this entry block is dependent on viral Env proteins. Laboratory-adapted HIV-1 strains are sensitive, whereas primary isolates are highly resistant to SERINC5. Env proteins mediate virus entry via extensive conformational rearrangements from a closed ground state to a CD4-bound open state. We detected Env-Env associations and Env-SERINC5 interactions in live cells by a novel bimolecular fluorescence assay. We demonstrate that CD4 expression increases the Env sensitivity to SERINC5 and allows SERINC5 to dissociate the Env complex, suggesting that SERINC5 restriction is dependent on Env conformation. Our results provide new insights into the poorly defined Env-dependent SERINC5 antiviral mechanism.

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Section: Resultsmentioning

confidence: 99%

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CD4 Expression and Env Conformation Are Critical for HIV-1 Restriction by SERINC5

Zhang

Shi

Qiu

et al. 2019

J Virol

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“…The HIV-1 accessory protein Nef, which is essential for the generation of fully infectious HIV-1 particles, especially in selected lymphoid T-cell lines (1) and primary T cells (2), antagonizes the restriction imposed by cellular SERINC5 (3, 4) and, to a lesser extent, SERINC3 (4) proteins. Murine leukemia virus (MLV) and equine infectious anemia virus (EIAV) have evolved cognate SERINC5-counteracting factors, glyco-Gag and S2, respectively (3, 5–8), illustrating the importance of developing antagonistic strategies against SERINC5 during virus evolution. The antiviral mode of action of SERINC5 and the mechanisms of Nef-mediated counteraction have been addressed in several studies using heterologous expression systems based on transient overexpression and genetic knockout systems (3, 4, 9–18).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Endogenous SERINC5 Protein as Anti-HIV-1 Factor

Passos

Zillinger

Casartelli

et al. 2019

J Virol

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SERINC5 is the long-searched-for antiviral factor that is counteracted by the HIV-1 accessory gene product Nef. Here, we engineered, via CRISPR/Cas9 technology, T-cell lines that express endogenous SERINC5 alleles tagged with a knocked-in HA epitope. This genetic modification enabled us to study basic properties of endogenous SERINC5 and to verify proposed mechanisms of HIV-1 Nef-mediated counteraction of SERINC5. Using this unique resource, we identified the susceptibility of endogenous SERINC5 protein to posttranslational modulation by type I IFNs and suggest uncoupling of Nef-mediated functional antagonism from SERINC5 exclusion from virions.

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“…Three distinct genera of retroviruses were reported to have independently come up with antagonizing factors to elude the inhibition by SERINC 5. Having no activity in Nef and Glycogag against coelacanth SERINC 2 (Fig-3A and 3B) whether represents a new case of functional arms-race dynamics is what we wanted to check next (16–18,22) (Fig-3E) . We learnt that coelacanth fish has an endogenous foamy virus (23) the genome organization of which resembled the prototype foamy virus ( Fig-4A ).…”

Section: Resultsmentioning

confidence: 99%

“…Is this another functional evidence for arms-race dynamics as three distinct genera of retroviruses are reported to have independently come up with antagonizing factors ? (16–18,22) (Fig-3E). We learnt that coelacanth fish has an endogenous foamy virus (23) the genome organization of which resembled the prototype foamy virus (Fig-4A).…”

Section: Resultsmentioning

confidence: 99%

Coevolution of retroviruses withSERINCs following whole-genome duplication divergence

Ramdas

Bhardwaj

Singh

et al. 2020

Preprint

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9The SERINC gene family comprises of five paralogs in humans of which SERINC3 and 10 SERINC5 inhibit HIV-1 infectivity and are counteracted by Nef. The origin of this anti-retroviral 11 activity, its prevalence among the remaining human paralogs, and its ability to target 12 retroviruses remain largely unknown. Here we show that despite their early divergence, the 13 anti-retroviral activity is functionally conserved among four human SERINC paralogs with 14 SERINC2 being an exception. The lack of activity in human SERINC2 is associated with its 15 post-whole genome duplication (WGD) divergence, as evidenced by the ability of pre-WGD 16 orthologs from yeast, fly, and a post-WGD-proximate SERINC2 from coelacanth to inhibit nef-17 defective HIV-1. Intriguingly, potent retroviral factors from HIV-1 and MLV are not able to relieve 18 the SERINC2-mediated particle infectivity inhibition, indicating that such activity was directed 19 towards other retroviruses that are found in coelacanth (like foamy viruses). However, foamy-20 derived vectors are intrinsically resistant to the action of SERINC2, and we show that a foamy 21 virus envelope confers this resistance. Despite the presence of weak arms-race signatures, the 22 functional reciprocal adaptation among SERINC2 and SERINC5 and, in response, the 23 emergence of antagonizing ability in foamy virus appears to have resulted from a long-term 24 conflict with the host. 25 26 27 28 Introduction 29Viruses have been exploiting the host machinery for their persistence, and, in response, the 30 host has continued to evolve increasingly intricate antiviral defense strategies. As part of this 31 ongoing arms-race, while viruses have relied on acquisition and fusion of diverse genes (1), 32 the host-defense mechanism has been made possible by the functional divergence of gene 33 copies following duplication of genes as well as whole-genomes (2-7). Restriction factors being 34 at the forefront of this long-term conflict (8-10), show clear molecular signatures of arms-race 35 (11,12). In fact, the presence of these signatures has been proposed to be a hallmark of 36 restriction factors (8,13), and has been used as a screening strategy to identify potential 37 candidates (2,14). In contrast, the recently identified anti-retroviral host inhibitors SERINC5 and 38 SERINC3 display an uneventful evolutionary history (15). This is counterintuitive, because 39 distant retroviruses, with wide host-range, encode anti-SERINC5 virulent factors (16)(17)(18). We, 40Ramdas et al.therefore, sought to trace the origins of this antiretroviral activity and its relevance for retroviral 41 inhibition. Our analysis to comprehend the evolutionary origins of the antiretroviral activity in 42 SERINCs, identifies an active SERINC2 with a hitherto unknown interaction with a foamy virus. 44 Results 45Antiretroviral activity among human SERINC paralogs 46 Analysis of sequence similarity and gene structure conservation reveals that SERINC5 and 47 SERINC4 share a recent ancestry (Fig-S1). Similarly, SERINC3 and...

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The retroviral accessory proteins S2, Nef, and glycoMA use similar mechanisms for antagonizing the host restriction factor SERINC5

Cited by 29 publications

References 29 publications

CD4 Expression and Env Conformation Are Critical for HIV-1 Restriction by SERINC5

CD4 Expression and Env Conformation Are Critical for HIV-1 Restriction by SERINC5

Characterization of Endogenous SERINC5 Protein as Anti-HIV-1 Factor

Coevolution of retroviruses withSERINCs following whole-genome duplication divergence

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