Human HERC5 restricts an early stage of HIV-1 assembly by a mechanism correlating with the ISGylation of Gag

Woods, Matthew; Kelly, Jenna N.; Hattlmann, Clayton J.; Tong, Jessica; Xu, Li; Coleman, Macon D.; Quest, Graeme; Smiley, James R.; Barr, Stephen D.

doi:10.1186/1742-4690-8-95

Cited by 69 publications

(82 citation statements)

References 57 publications

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“…Because ISGylation has been reported to inhibit HIV-1 budding and release (Okumura et al, 2006; Pincetic et al, 2010; Woods et al, 2011), we evaluated the role of UBE2L6 in HIV-1 late-stage replication. We observed >65% inhibition of virion release 72 hr post-infection in UBE2L6-expressing cells as compared to cells expressing the vector control.…”

Section: Resultsmentioning

confidence: 99%

“…Host protein ISGylation has been implicated in cellular activities that restrict HIV-1 infection. Specifically, studies have demonstrated that HERC5, the E3 ligase component of the ISGylation machinery, reduces HIV-1 virion production through the aggregation of Gag at viral assembly sites in the membrane, which is distinct from the mechanism involving free ISG15 that results in Gag aggregation in both membrane and cytosolic regions of the cell (Woods et al, 2011). Additional mechanisms such as the inhibition of Gag and Tsg101 interaction by ISG15 (Okumura et al, 2006) have been implicated in regulating late-stage HIV-1 replication.…”

Section: Discussionmentioning

confidence: 99%

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Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu

et al. 2018

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SUMMARY Accessory proteins of lentiviruses, such as HIV-1, target cellular restriction factors to enhance viral replication. Systematic analyses of proteins that are targeted for degradation by HIV-1 accessory proteins may provide a better understanding of viral immune evasion strategies. Here, we describe a high-throughput platform developed to study cellular protein stability in a highly parallelized matrix format. We used this approach to identify cellular targets of the HIV-1 accessory protein Vpu through arrayed coexpression with 433 interferon-stimulated genes, followed by differential fluorescent labeling and automated image analysis. Among the previously unreported Vpu targets identified by this approach, we find that the E2 ligase mediating ISG15 conjugation, UBE2L6, and the transmembrane protein PLP2 are targeted by Vpu during HIV-1 infection to facilitate late-stage replication. This study provides a framework for the systematic and high-throughput evaluation of protein stability and establishes a more comprehensive portrait of cellular Vpu targets.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu

et al. 2018

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“…This inhibition of replication was dependent on the ability of ISG15 to form conjugates as increased influenza B virus replication was also seen in mice that lack the ISG15 E1 activating enzyme, UbE1L, and thus fail to form ISG15 conjugates (24). Subsequent studies have demonstrated that ISG15 can antagonize the replication of vaccinia virus, influenza A virus, Sendai virus, human papillomavirus, Ebola virus, and HIV-1 in tissue culture to various degrees (23,(25)(26)(27)(28)(29)(30)(31)(32)(33).…”

mentioning

confidence: 99%

Novel Mode of ISG15-Mediated Protection against Influenza A Virus and Sendai Virus in Mice

Morales

Monte

Sun

et al. 2015

J Virol

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ISG15 is a diubiquitin-like modifier and one of the most rapidly induced genes upon type I interferon stimulation. Hundreds of host proteins and a number of viral proteins have been shown to be ISGylated, and understanding how these modifications affect the interferon response and virus replication has been of considerable interest. ISG15؊/؊ mice exhibit increased susceptibility to viral infection, and in the case of influenza B virus and vaccinia virus, ISG15 conjugation has been shown to restrict virus replication in vivo. A number of studies have also found that ISG15 is capable of antagonizing replication of some viruses in tissue culture. However, recent findings have demonstrated that ISG15 can protect mice from Chikungunya virus infection without affecting the virus burden. In order to better understand the function of ISG15 in vivo, we characterized the pathogenesis of influenza A virus and Sendai virus in ISG15 ؊/؊ mice. We found that ISG15 protects mice from virus induced lethality by a conjugation-dependent mechanism in both of these models. However, surprisingly, we found that ISG15 had minimal effect on virus replication and did not have an obvious role in the modulation of the acute immune response to infection. Instead, we observed an increase in the number of diseased small airways in mice lacking ISG15. This ability of ISG15 to protect mice in a conjugationdependent, but nonantiviral, manner from respiratory virus infection represents a previously undescribed role for ISG15 and demonstrates the importance of further characterization of ISG15 in vivo. IMPORTANCE It has previously been demonstrated that ISG15؊/؊ mice are more susceptible to a number of viral infections. Since ISG15 is one of the most strongly induced genes after type I interferon stimulation, analysis of ISG15 function has largely focused on its role as an antiviral molecule during acute infection. Although a number of studies have shown that ISG15 does have a small effect on virus replication in tissue culture, few studies have confirmed this mechanism of protection in vivo. In these studies we have found that while ISG15 ؊/؊ mice are more susceptible to influenza A virus and Sendai virus infections, ISGylation does not appear to mediate this protection through the direct inhibition of virus replication or the modulation of the acute immune response. Thus, in addition to showing a novel mode of ISG15 mediated protection from virus infection, this study demonstrates the importance of studying the role of ISG15 in vivo. During acute infection, the survival of an organism is dependent on both its ability to inhibit pathogen replication, thus reducing pathogen burden, and its ability to tolerate the ensuing tissue damage incurred both from the pathogen itself, as well as from the immune response mounted against the pathogen (1, 2). Limiting pathogen replication and eventual pathogen clearance is dependent on both the innate and the adaptive immune responses. Of the many genes induced after viral infection, type I interferons ...

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“…HERC5 is a ligase that targets newly synthesized proteins for ISG15 conjugation and facilitates many cellular pathways. Woods et al showed that overexpression of HERC5 induced a fourfold decrease in HIV production in 293T cells and HERC5 knockdown doubled viral production (Woods et al 2011). By transmission electron microscopy, it was shown that HERC5 blocks an early step of HIV-1 particle assembly at the plasma membrane.…”

Section: Gag Assembly: Herc5mentioning

confidence: 97%

Cell-Intrinsic Immunity

Elinav

Sutton

2014

Encyclopedia of AIDS

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Human HERC5 restricts an early stage of HIV-1 assembly by a mechanism correlating with the ISGylation of Gag

Cited by 69 publications

References 57 publications

Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu

Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu

Novel Mode of ISG15-Mediated Protection against Influenza A Virus and Sendai Virus in Mice

Cell-Intrinsic Immunity

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