Regulation of CD4 Expression via Recycling by HRES-1/RAB4 Controls Susceptibility to HIV Infection

Nagy, György; Ward, Jeffrey P.; Mosser, Dick D.; Koncz, Ágnes; Gergely, P; Stancato, Christina; Qian, Yueming; Fernández, David; Niland, Brian; Grossman, Craig E.; Telarico, Tiffany; Bánki, Katalin; Perl, András

doi:10.1074/jbc.m606301200

Cited by 62 publications

(120 citation statements)

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“…By contrast, surface expression of CD4 was enhanced by dominant-negative HRES-1/Rab4 S27N . As controls, HIV co-receptor fusin/CXCR4 and CD45RO were not influenced by HRES-1/Rab4 [55]. Coordinate suppression by HRES-1/ Rab4 and upregulation by HRES-1/Rab4 S27N indicated a specific role for HRES-1/Rab4 in regulation of CD4 expression.…”

mentioning

confidence: 85%

“…HRES-1/Rab4 codes for five additional amino acids and two discordant residues, 163 (D → N) and 209 (T → A) [55]. Since, the HRES-1 is a single copy sequence in the haploid genome [60], the previously identified Rab4a may originate from another chromosomal locus or correspond to an alternative translation product of the polymorphic HRES-1/Rab4 genomic locus.…”

Section: Hres-1/rab4 Regulates Hiv Infection Via Recycling Of Cd4mentioning

confidence: 99%

“…We cloned a novel 2986 base long cDNA (Genbank accession number: AY585832) corresponding to the antisense strand of the HRES-1 locus [55]. This cDNA sequence has considerable homology to the 735 base long Rab4a gene (Genbank accession number: M28211.gb_pr1) and was termed HRES-1/Rab4.…”

Section: Hres-1/rab4 Regulates Hiv Infection Via Recycling Of Cd4mentioning

confidence: 99%

“…This cDNA sequence has considerable homology to the 735 base long Rab4a gene (Genbank accession number: M28211.gb_pr1) and was termed HRES-1/Rab4. The 5′ and 3′ untranslated regions in the HRES-1/Rab4 cDNA were markedly different from those of Rab4a [55].HRES-1/Rab4 codes for five additional amino acids and two discordant residues, 163 (D → N) and 209 (T → A) [55]. Since, the HRES-1 is a single copy sequence in the haploid genome [60], the previously identified Rab4a may originate from another chromosomal locus or correspond to an alternative translation product of the polymorphic HRES-1/Rab4 genomic locus.…”

mentioning

confidence: 99%

“…HRES-1 was previously mapped to human chromosome 1q42 [60]. All eight coding exons of the HRES-1/Rab4 cDNA were localized within contig NT 031728.1 mapped to the 1q42 genomic locus [55]. Bidirectional transcription has been previously documented at several genomic loci [93,94] Rab4a has been shown to regulate recycling of early endosomes carrying the TFR in epithelial cells [97] or GLUT4 in adipocytes [98].…”

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Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE

et al. 2008

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Genetic and environmental factors are believed to influence development of systemic lupus erythematosus (SLE). Endogenous retroviruses (ERV) correspond to the integrated proviral form of infectious retroviruses, which are trapped within the genome due to mutations. ERV represent a key molecular link between the host genome and infectious viral particles. ERV-encoded proteins are recognized by antiviral immune responses and become targets of autoreactivity. Alternatively, ERV protein may influence cellular processes and the life cycle of infectious viruses. As examples, the HRES-1 human ERV encodes a 28-kDa nuclear autoantigen and a 24-kDa small GTP-ase, termed HRES-1/Rab4. HRES-1/p28 is a nuclear autoantigen recognized by crossreactive antiviral antibodies, while HRES-1/Rab4 regulates surface expression of CD4 and the transferrin receptor (TFR) through endosome recycling. Expression of HRES-1/Rab4 is induced by the tat gene of HIV-1, which in turn down-regulates expression of CD4 and susceptibility to reinfection by HIV-1. CD4 and the TFR play essential roles in formation of the immunological synapse (IS) during normal T-cell activation by a cognate MHC class II peptide complex. The key intracellular transducer of T-cell activation, Lck, is brought to the IS via binding to CD4. T-cell receptorζ (TCRζ) chain binds to the TFR. Abnormal T-cell responses in SLE have been associated with reduced lck and TCRζ chain levels. HRES-1 is centrally located on chromosome 1 at q42 relative to lupus-linked microsatellite markers and polymorphic HRES-1 alleles have been linked to the development of SLE. 1q42 is one of the three most common fragile sites in the human genome, and is inducible by DNA demethylation, a known mechanism of retroviral gene activation. Molecular mimicry and immunomodulation by a ERV, such as HRES-1, may contribute to self-reactivity and abnormal Tand B-cell functions in SLE. (Table I). HERVs are commonly designated as HERV followed by a single letter amino acid code corresponding to a tRNA. The 3′ terminus of tRNA is predicted to initiate reverse transcription by annealing to an 18 nucleotide long primer-binding site (PBS) at the 5′ LTR. While expression of murine ERV can lead to production of infectious virus and cause viremia, no production of infectious virion has been documented by HERV. High copy number of most ERV families makes it difficult to distinguish which members of a group are expressed. Although, no single provirus with intact LTRs and uninterrupted gag, pol, and env ORFs has been identified, the HERV-K ERV, as a family, has been shown to encode gag HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript the LTR region, is functionally analogous to the HIV-1 rev and HTLV-I/II rex proteins. HERV-K rev binds to both the nuclear export factor Crm1 and to a cis-acting viral RNA to activate nuclear export of unspliced RNAs [39]. Alternatively, the HERV-K LTR is also recognized by HIV-1 rev, suggesting a potential interaction between these exogeneous a...

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Section: Hres-1/rab4 Regulates Hiv Infection Via Recycling Of Cd4mentioning

confidence: 99%

Section: Hres-1/rab4 Regulates Hiv Infection Via Recycling Of Cd4mentioning

confidence: 99%

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Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE

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Redox Pathogenesis in Rheumatic Diseases

Laniak,

Winans,

Patel

et al. 2024

ACR Open Rheumatology

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Despite being some of the most anecdotally well‐known roads to pathogenesis, the mechanisms governing autoimmune rheumatic diseases are not yet fully understood. The overactivation of the cellular immune system and the characteristic development of autoantibodies have been linked to oxidative stress. Typical clinical manifestations, such as joint swelling and deformities and inflammation of the skin and internal organs, have also been connected directly or indirectly to redox mechanisms. The differences in generation and restraint of oxidative stress provide compelling evidence for the broad variety in pathology among rheumatic diseases and explain some of the common triggers and discordant manifestations in these diseases. Growing evidence of redox mechanisms in pathogenesis has provided a broad array of new potential therapeutic targets. Here, we explore the mechanisms by which oxidative stress is generated, explore its roles in autoimmunity and end‐organ damage, and discuss how individual rheumatic diseases exhibit unique features that offer targets for therapeutic interventions.

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Haplotypes of the HRES‐1 endogenous retrovirus are associated with development and disease manifestations of systemic lupus erythematosus

Pullmann¹,

Bonilla²,

Phillips³

et al. 2008

Arthritis & Rheumatism

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Objective. Endogenous retroviral sequences represent a link between viral and genetic factors that may influence the development of systemic lupus erythematosus (SLE). The HRES-1 human endogenous retroviral sequence is centrally located at the 1q42 chromosomal region relative to microsatellites previously associated with SLE. We therefore undertook the present study to determine the haplotypes of the HRES-1 locus and their linkage to SLE.Methods. One hundred six patients with SLE, 82 unrelated healthy Caucasian individuals, and 70 healthy members of 34 lupus families were examined. HRES-1 was amplified by polymerase chain reaction (PCR) and analyzed by sequencing and restriction enzyme mapping. Microsatellites were analyzed by PCR. Haplotype construction and transmission disequilibrium testing (TDT) were performed in lupus families.Results. Based on 4 single-nucleotide polymorphisms (SNPs) within a 935-base interval, we detected 6 HRES-1 haplotypes that were differentially segregated in unrelated Caucasian patients and control subjects ( 2 ‫؍‬ 16.86, P ‫؍‬ 0.0048) and were in linkage disequilibrium (LD) with the D1S225 microsatellite (P ‫؍‬ 0.0002). The microsatellites D1S225, D1S235, and D1S2785 (but not D1S229) were linked to SLE by TDT. Interestingly, LD between HRES-1 SNPs at bases 653 and 1259 was reduced in patients with SLE (P ‫؍‬ 0.048). The HRES-1 653C/1259C-harboring alleles were associated with the presence of renal disease (P ‫؍‬ 0.0021) and with the absence of lung disease (P ‫؍‬ 0.0323), while the 956A allele was associated with the antiphospholipid syndrome in patients with SLE (P ‫؍‬ 0.0036).Conclusion. The HRES-1 locus represents a recombination hot spot at the 1q42 chromosomal region that influences the development and disease manifestations of SLE.

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Regulation of CD4 Expression via Recycling by HRES-1/RAB4 Controls Susceptibility to HIV Infection

Cited by 62 publications

References 51 publications

Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE

Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE

Redox Pathogenesis in Rheumatic Diseases

Haplotypes of the HRES‐1 endogenous retrovirus are associated with development and disease manifestations of systemic lupus erythematosus

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