The Adenovirus E3 RID Complex Protects Some Cultured Human T and B Lymphocytes from Fas-Induced Apoptosis

McNees, Adrienne L.; Garnett, C. T.; Gooding, Linda R.

doi:10.1128/jvi.76.19.9716-9723.2002

Cited by 28 publications

(26 citation statements)

References 32 publications

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“…Ads establish longterm, latent infections of mucosal lymphocytes associated with intermittent virus shedding in stool (89). It has been suggested that E3 proteins, including RID␣, prevent the elimination of persistently infected lymphocytes by downregulating expression of receptors involved in innate immune responses (90). Our results suggest that RID␣ may also induce limited changes in gene expression that mimic a developmental program regulating B cell differentiation, by upregulating constitutive NF-B activity in persistently infected lymphocytes.…”

Section: Discussionmentioning

confidence: 58%

Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

Cianciola

Chung

Manor

et al. 2017

J Virol

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Human adenoviruses (Ads) generally cause mild self-limiting infections but can lead to serious disease and even be fatal in high-risk individuals, underscoring the importance of understanding how the virus counteracts host defense mechanisms. This study had two goals. First, we wished to determine the molecular basis of cholesterol homeostatic responses induced by the early region 3 membrane protein RID␣ via its direct interaction with the sterol-binding protein ORP1L, a member of the evolutionarily conserved family of oxysterol-binding protein (OSBP)-related proteins (ORPs). Second, we wished to determine how this interaction regulates innate immunity to adenovirus. ORP1L is known to form highly dynamic contacts with endoplasmic reticulum-resident VAP proteins that regulate late endosome function under regulation of Rab7-GTP. Our studies have demonstrated that ORP1L-VAP complexes also support transport of LDL-derived cholesterol from endosomes to the endoplasmic reticulum, where it was converted to cholesteryl esters stored in lipid droplets when ORP1L was bound to RID␣. The virally induced mechanism counteracted defects in the predominant cholesterol transport pathway regulated by the late endosomal membrane protein Niemann-Pick disease type C protein 1 (NPC1) arising during early stages of viral infection. However, unlike NPC1, RID␣ did not reconstitute transport to endoplasmic reticulum pools that regulate SREBP transcription factors. RID␣-induced lipid trafficking also attenuated proinflammatory signaling by Toll-like receptor 4, which has a central role in Ad pathogenesis and is known to be tightly regulated by cholesterol-rich "lipid rafts." Collectively, these data show that RID␣ utilizes ORP1L in a way that is distinct from its normal function in uninfected cells to fine-tune lipid raft cholesterol that regulates innate immunity to adenovirus in endosomes.IMPORTANCE Early region 3 proteins encoded by human adenoviruses that attenuate immune-mediated pathology have been a particularly rich source of information regarding intracellular protein trafficking. Our studies with the early region 3-encoded RID␣ protein also provided fundamental new information regarding mechanisms of nonvesicular lipid transport and the flow of molecular information at membrane contacts between different organelles. We describe a new pathway that delivers cholesterol from endosomes to the endoplasmic reticulum, where it is esterified and stored in lipid droplets. Although lipid droplets are attracting renewed interest from the standpoint of normal physiology and human diseases, including those resulting from viral infections, experimental model systems for evaluating how and why they accumulate are still limited. Our studies also revealed an intriguing relationship between lipid droplets and innate immunity that may represent a new paradigm for viruses utilizing these organelles.KEYWORDS adenoviruses, cholesterol, endocytic pathway, endoplasmic reticulum, lipid droplet

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Section: Discussionmentioning

confidence: 58%

Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

Cianciola

Chung

Manor

et al. 2017

J Virol

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“…Retroviruses were produced as described previously (41). Briefly, the vector control LXSN or the LXSN-CAR plasmids were transfected into BOSC23 cells using FuGene6 transfection reagent (Roche) following the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

Postinternalization Inhibition of Adenovirus Gene Expression and Infectious Virus Production in Human T-Cell Lines

McNees

Mahr

Ornelles

et al. 2004

J Virol

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“…The HAdV-C E3 14.7K protein inhibits cell lysis by tumor necrosis factor alpha (TNF-␣) and lymphotoxin (54)(55)(56). CR1␣, RID␣, and RID␤ cooperate to evade TNF-␣-related apoptosis through TRAIL (57)(58)(59)(60), and the RID complex independently mediates loss of cell surface Fas (58,61), blocks TNF-␣-induced NF-B activation (62)(63)(64), and downregulates the epidermal growth factor receptor (40,65). HAdV-C CR1␤ (66), also called the adenovirus death protein, is expressed at greatest abundance late in infection (67) and is required for efficient cell lysis (68) and viral spread (69) in the final phase of viral infection.…”

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confidence: 99%

Homologous Recombination in E3 Genes of Human Adenovirus Species D

Singh

Robinson

Dehghan

et al. 2013

J Virol

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e Genes within the E3 transcription unit of human adenoviruses modulate host immune responses to infection. A comprehensive genomics and bioinformatics analysis of the E3 transcription unit for 38 viruses within human adenovirus species D (HAdV-D) revealed distinct and surprising patterns of homologous recombination. Homologous recombination was identified in open reading frames for E3 CR1␣, CR1␤, and CR1␥, similar to that previously observed with genes encoding the three major structural capsid proteins, the penton base, hexon, and fiber.

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The Adenovirus E3 RID Complex Protects Some Cultured Human T and B Lymphocytes from Fas-Induced Apoptosis

Cited by 28 publications

References 32 publications

Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

Postinternalization Inhibition of Adenovirus Gene Expression and Infectious Virus Production in Human T-Cell Lines

Homologous Recombination in E3 Genes of Human Adenovirus Species D

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