Novel Role of HSP40/DNAJ in the Regulation of HIV-1 Replication

Urano, Emiko; Morikawa, Yuko; Komano, Jun

doi:10.1097/qai.0b013e31829a2ef8

Cited by 22 publications

(20 citation statements)

References 41 publications

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“…Chaperone HSPA4 (HSP70) inhibits viral gene expression and replication [ 108 ]. Its co-chaperone DNAJ (HSP40) has been associated with both activation and inhibition of viruses, including HIV [ 109 ]. Ubiquitination by TRIM25 increases the ability of RIG-1 to initiate antiviral signaling by facilitating its interaction with MAVS.…”

Section: Discussionmentioning

confidence: 99%

The Broad-Spectrum Antiviral Protein ZAP Restricts Human Retrotransposition

et al. 2015

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Intrinsic immunity describes the set of recently discovered but poorly understood cellular mechanisms that specifically target viral pathogens. Their discovery derives in large part from intensive studies of HIV and SIV that revealed restriction factors acting at various stages of the retroviral life cycle. Recent studies indicate that some factors restrict both retroviruses and retrotransposons but surprisingly in ways that may differ. We screened known interferon-stimulated antiviral proteins previously untested for their effects on cell culture retrotransposition. Several factors, including BST2, ISG20, MAVS, MX2, and ZAP, showed strong L1 inhibition. We focused on ZAP (PARP13/ZC3HAV1), a zinc-finger protein that targets viruses of several families, including Retroviridae, Tiloviridae, and Togaviridae, and show that ZAP expression also strongly restricts retrotransposition in cell culture through loss of L1 RNA and ribonucleoprotein particle integrity. Association of ZAP with the L1 ribonucleoprotein particle is supported by co-immunoprecipitation and co-localization with ORF1p in cytoplasmic stress granules. We also used mass spectrometry to determine the protein components of the ZAP interactome, and identified many proteins that directly interact and colocalize with ZAP, including MOV10, an RNA helicase previously shown to suppress retrotransposons. The detection of a chaperonin complex, RNA degradation proteins, helicases, post-translational modifiers, and components of chromatin modifying complexes suggest mechanisms of ZAP anti-retroelement activity that function in the cytoplasm and perhaps also in the nucleus. The association of the ZAP ribonucleoprotein particle with many interferon-stimulated gene products indicates it may be a key player in the interferon response.

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Section: Discussionmentioning

confidence: 99%

The Broad-Spectrum Antiviral Protein ZAP Restricts Human Retrotransposition

et al. 2015

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“…MRJ-S mainly localizes to the cytoplasm while MRJ-L distributes both to the cytosol and the nucleus ( Cheetham et al, 1992 ). It has been suggested that the conserved DNAJ domain was responsible for HSP40's ability to inhibit HIV-1 production ( Urano et al, 2013 ). Our results show that a significant correlation is found between levels of macrophage MRJ-L expression and levels of HIV-1 infection among high-risk subjects.…”

Section: Discussionmentioning

confidence: 99%

Large Isoform of Mammalian Relative of DnaJ is a Major Determinant of Human Susceptibility to HIV-1 Infection

et al. 2014

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SummaryIndividual differences in susceptibility to human immunodeficiency virus type 1 (HIV-1) infection have been of interest for decades. We aimed to determine the contribution of large isoform of Mammalian DnaJ (MRJ-L), a HIV-1 Vpr-interacting cellular protein, to this natural variation. Expression of MRJ-L in monocyte-derived macrophages was significantly higher in HIV-infected individuals (n = 31) than their uninfected counterparts (n = 27) (p = 0.009). Fifty male homosexual subjects (20 of them are HIV-1 positive) were further recruited to examine the association between MRJ-L levels and occurrence of HIV infection. Bayesian multiple logistic regression revealed that playing a receptive role and increased levels of MRJ-L in macrophages were two risk factors for HIV-1 infection. A 1% rise in MRJ-L expression was associated with a 1.13 fold (95% CrI 1.06–1.29) increase in odds of contracting HIV-1 infection. Ex vivo experiments revealed that MRJ-L facilitated Vpr-dependent nuclear localization of virus. Infection of macrophage-tropic strain is a critical step in HIV-1 transmission. MRJ-L is a critical factor in this process; hence, subjects with higher macrophage MRJ-L levels are more vulnerable to HIV-1 infection.

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“…The identification of DNAJB12 as a potentially important gene is reminiscent of the observation that the HSP40/DNAJ family proteins play a role in infection of various viruses. Urano and colleagues identified DNAJ/HSP40B6 as a potential regulator of HIV-1 replication [ 40 ]. It is an interesting finding considering the attention that another chaperone, namely HSP90, has recently attracted: HSP90 could promote infectiousness of HIV by controlling HIV reactivation from latency [ 41 ] and several inhibitors of HSP90 are currently in clinical development [ 42 ].…”

Section: Resultsmentioning

confidence: 99%

Identification of Genes Whose Expression Profile Is Associated with Non-Progression towards AIDS Using eQTLs

et al. 2015

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BackgroundMany genome-wide association studies have been performed on progression towards the acquired immune deficiency syndrome (AIDS) and they mainly identified associations within the HLA loci. In this study, we demonstrate that the integration of biological information, namely gene expression data, can enhance the sensitivity of genetic studies to unravel new genetic associations relevant to AIDS.MethodsWe collated the biological information compiled from three databases of expression quantitative trait loci (eQTLs) involved in cells of the immune system. We derived a list of single nucleotide polymorphisms (SNPs) that are functional in that they correlate with differential expression of genes in at least two of the databases. We tested the association of those SNPs with AIDS progression in two cohorts, GRIV and ACS. Tests on permuted phenotypes of the GRIV and ACS cohorts or on randomised sets of equivalent SNPs allowed us to assess the statistical robustness of this method and to estimate the true positive rate.ResultsEight genes were identified with high confidence (p = 0.001, rate of true positives 75%). Some of those genes had previously been linked with HIV infection. Notably, ENTPD4 belongs to the same family as CD39, whose expression has already been associated with AIDS progression; while DNAJB12 is part of the HSP90 pathway, which is involved in the control of HIV latency. Our study also drew our attention to lesser-known functions such as mitochondrial ribosomal proteins and a zinc finger protein, ZFP57, which could be central to the effectiveness of HIV infection. Interestingly, for six out of those eight genes, down-regulation is associated with non-progression, which makes them appealing targets to develop drugs against HIV.

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Novel Role of HSP40/DNAJ in the Regulation of HIV-1 Replication

Abstract: This is the first report providing evidence that HSP70-HSP40 complex confers an innate resistance specific to HIV-1. For their interferon-inducible nature, HSP40 family members should account for the anti-HIV-1 function of interferon.

Cited by 22 publications

References 41 publications

The Broad-Spectrum Antiviral Protein ZAP Restricts Human Retrotransposition

The Broad-Spectrum Antiviral Protein ZAP Restricts Human Retrotransposition

Large Isoform of Mammalian Relative of DnaJ is a Major Determinant of Human Susceptibility to HIV-1 Infection

Identification of Genes Whose Expression Profile Is Associated with Non-Progression towards AIDS Using eQTLs

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