Mouse mammary tumor virus uses mouse but not human transferrin receptor 1 to reach a low pH compartment and infect cells

Wang, Enxiu; Obeng-Adjei, Nyamekye; Ying, Qihua; Meertens, Laurent; Dragic, Tanya; Davey, Robert A.; Ross, Susan R.

doi:10.1016/j.virol.2008.08.013

Cited by 44 publications

(39 citation statements)

References 46 publications

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“…Interestingly, although MACV uses hTfR1 for viral entry, it was relatively insensitive to TTP knockdown. This is similar to what has been observed with MMTV, which uses mouse TfR1 to enter cells but has been reported to be TTP-independent (12). Thus, dependence on TTP does seem to be functionally relevant and, to some extent, defines TTP as yet another cellular factor required for HCV entry.…”

Section: Discussionsupporting

confidence: 85%

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Identification of transferrin receptor 1 as a hepatitis C virus entry factor

Martin

Uprichard

2013

Proc. Natl. Acad. Sci. U.S.A.

193

175

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Hepatitis C virus (HCV) is a liver tropic pathogen that affects ∼170 million people worldwide and causes liver pathologies including fibrosis, cirrhosis, steatosis, iron overload, and hepatocellular carcinoma. As part of a project initially directed at understanding how HCV may disrupt cellular iron homeostasis, we found that HCV alters expression of the iron uptake receptor transferrin receptor 1 (TfR1). After further investigation, we found that TfR1 mediates HCV entry. Specifically, functional studies showed that TfR1 knockdown and antibody blocking inhibit HCV cell culture (HCVcc) infection. Blocking cell surface TfR1 also inhibited HCV pseudoparticle (HCVpp) infection, demonstrating that TfR1 acts at the level of HCV glycoprotein-dependent entry. Likewise, a TfR1 small-molecule inhibitor that causes internalization of surface TfR1 resulted in a decrease in HCVcc and HCVpp infection. In kinetic studies, TfR1 antibody blocking lost its inhibitory activity after anti-CD81 blocking, suggesting that TfR1 acts during HCV entry at a postbinding step after CD81. In contrast, viral spread assays indicated that HCV cellto-cell spread is less dependent on TfR1. Interestingly, silencing of the TfR1 trafficking protein, a TfR-1 specific adaptor protein required for TfR1 internalization, also inhibited HCVcc infection. On the basis of these results, we conclude that TfR1 plays a role in HCV infection at the level of glycoprotein-mediated entry, acts after CD81, and possibly is involved in HCV particle internalization.hepatic iron overload | viral entry factor H epatitis C virus (HCV) infects more than 170 million people worldwide. Approximately 80% of infections persist to chronicity and can lead to liver pathologies including fibrosis, cirrhosis, steatosis, hepatic iron overload, and hepatocellular carcinoma. At this time, however, no vaccine is available to protect against infection, and current IFN-based treatment options, including those that include the HCV protease inhibitors recently approved for genotype 1 patients, are associated with toxic side effects and are only effective in a subset of patients (1, 2). As a result, in the United States, chronic HCV infection is the leading cause of hepatocellular carcinoma and the most common indication for liver transplantation. Importantly, identifying host factors and pathways involved in HCV infection could provide insight into HCVmediated liver disease and possibly lead to the discovery of novel therapeutic targets.Previous studies have reported that a disproportionate number of HCV patients develop hepatic iron overload, suggesting that iron metabolic pathways are deregulated during HCV infection (3-6). Consistent with this hypothesis, changes in the expression of iron metabolic genes have been reported in infected patients and in one HCV replicon cell clone (7,8). Following up on those studies, we initially observed that TfR1 mRNA and protein levels were down-regulated in human hepatoma Huh7 cells in response to HCV infection.TfR1 is the main receptor for cellular ir...

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Section: Discussionsupporting

confidence: 85%

“…Interestingly, TfR1 has been identified as an entry receptor for several viruses, including the New World arenaviruses, Machupo virus (MACV) and Junin virus, mouse mammary tumor virus (MMTV), canine parvovirus, and feline panleukopenia virus (10)(11)(12).…”

mentioning

confidence: 99%

Identification of transferrin receptor 1 as a hepatitis C virus entry factor

Martin

Uprichard

2013

Proc. Natl. Acad. Sci. U.S.A.

193

175

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“…Beta-type ENVs are known to have restricted species tropism based on receptor usage; however, the range of cell types tested has been limited to those in which specific retroviruses can replicate (19,(22)(23)(24)(25)(26). Since the VSV core can replicate in all eukaryotic cells in culture, VSV-HERVK provides a unique reagent to interrogate more broadly the ability of HERV-K ENV to mediate entry into those cells.…”

Section: Resultsmentioning

confidence: 99%

“…SU contains the receptor-binding site, and TM contains the fusion machinery, along with a transmembrane domain and cytoplasmic tail of variable length. All betaretroviral ENVs tested (those of MMTV, JSRV, and ENTV) require endosomal uptake and acidification to mediate membrane fusion and infection (19)(20)(21).…”

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confidence: 99%

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Infectious Entry Pathway Mediated by the Human Endogenous Retrovirus K Envelope Protein

Robinson

Whelan

2016

J Virol

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Endogenous retroviruses (ERVs), the majority of which exist as degraded remnants of ancient viruses, comprise approximately 8% of the human genome. The youngest human ERVs (HERVs) belong to the HERV-K(HML-2) subgroup and were endogenized within the past 1 million years. The viral envelope protein (ENV) facilitates the earliest events of endogenization (cellular attachment and entry), and here, we characterize the requirements for HERV-K ENV to mediate infectious cell entry. Cell-cell fusion assays indicate that a minimum of two events are required for fusion, proteolytic processing by furin-like proteases and exposure to acidic pH. We generated an infectious autonomously replicating recombinant vesicular stomatitis virus (VSV) in which the glycoprotein was replaced by HERV-K ENV. HERV-K ENV imparts an endocytic entry pathway that requires dynamin-mediated membrane scission and endosomal acidification but is distinct from clathrin-dependent or macropinocytic uptake pathways. The lack of impediments to the replication of the VSV core in eukaryotic cells allowed us to broadly survey the HERV-K ENV-dictated tropism. Unlike extant betaretroviral envelopes, which impart a narrow species tropism, we found that HERV-K ENV mediates broad tropism encompassing cells from multiple mammalian and nonmammalian species. We conclude that HERV-K ENV dictates an evolutionarily conserved entry pathway and that the restriction of HERV-K to primate genomes reflects downstream stages of the viral replication cycle. IMPORTANCEApproximately 8% of the human genome is of retroviral origin. While many of those viral genomes have become inactivated, some copies of the most recently endogenized human retrovirus, HERV-K, can encode individual functional proteins. Here, we characterize the envelope protein (ENV) of the virus to define how it mediates infection of cells. We demonstrate that HERV-K ENV undergoes a proteolytic processing step and triggers membrane fusion in response to acidic pH-a strategy common to many viral fusogens. Our data suggest that the infectious entry pathway mediated by this ENV requires endosomal acidification and the GTPase dynamin but does not require clathrin-dependent uptake. In marked contrast to other betaretroviruses, HERV-K ENV imparts broad species tropism in cultured cells. This work provides new insights into the entry pathway of an extinct human virus and provides a powerful tool to further probe the endocytic route by which HERV-K infects cells. E ndogenous retroviruses (ERVs) comprise approximately 8% of the human genome (1). Such ERVs provide a physical record of ancient infections by once exogenous retroviruses; however, the degraded states of most sequences largely obscure their biological properties. Consequently, relatively little is known about the earliest events of endogenization, including how the viruses initially entered the germ line to become vertically transmitted elements. The process of endogenization begins with cellular attachment and viral entry, which is mediated by the envel...

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Mouse Mammary Tumor Virus and Cancer

Ross

2011

Cancer Associated Viruses

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Mouse mammary tumor virus uses mouse but not human transferrin receptor 1 to reach a low pH compartment and infect cells

Cited by 44 publications

References 46 publications

Identification of transferrin receptor 1 as a hepatitis C virus entry factor

Identification of transferrin receptor 1 as a hepatitis C virus entry factor

Infectious Entry Pathway Mediated by the Human Endogenous Retrovirus K Envelope Protein

Mouse Mammary Tumor Virus and Cancer

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