HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis.
The multifunctional Nef protein of HIV-1 is important for the progression to AIDS. One action of Nef is to down-regulate surface MHC I molecules, helping infected cells to evade immunity. We found that Nef also down-regulates the macrophage-expressed MHC 1b protein HFE, which regulates iron homeosta...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2005
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| _version_ | 1797105226544578560 |
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| author | Drakesmith, H Chen, N Ledermann, H Screaton, G Townsend, A Xu, X |
| author_facet | Drakesmith, H Chen, N Ledermann, H Screaton, G Townsend, A Xu, X |
| author_sort | Drakesmith, H |
| collection | OXFORD |
| description | The multifunctional Nef protein of HIV-1 is important for the progression to AIDS. One action of Nef is to down-regulate surface MHC I molecules, helping infected cells to evade immunity. We found that Nef also down-regulates the macrophage-expressed MHC 1b protein HFE, which regulates iron homeostasis and is mutated in the iron-overloading disorder hemochromatosis. In model cell lines, Nef reroutes HFE to a perinuclear structure that overlaps the trans-Golgi network, causing a 90% reduction of surface HFE. This activity requires a Src-kinase-binding proline-rich domain of Nef and a conserved tyrosine-based motif in the cytoplasmic tail of HFE. HIV-1 infection of ex vivo macrophages similarly down-regulates naturally expressed surface HFE in a Nef-dependent manner. The effect of Nef expression on cellular iron was explored; iron and ferritin accumulation were increased in HIV-1-infected ex vivo macrophages expressing wild-type HFE, but this effect was lost with Nef-deleted HIV-1 or when infecting macrophages from hemochromatosis patients expressing mutated HFE. The iron accumulation in HIV-1-infected HFE-expressing macrophages was paralleled by an increase in cellular HIV-1-gag expression. We conclude that, through Nef and HFE, HIV-1 directly regulates cellular iron metabolism, possibly benefiting viral growth. |
| first_indexed | 2024-03-07T06:44:28Z |
| format | Journal article |
| id | oxford-uuid:fa647727-1d36-4cc1-a76c-f805b6a8f7ec |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:44:28Z |
| publishDate | 2005 |
| record_format | dspace |
| spelling | oxford-uuid:fa647727-1d36-4cc1-a76c-f805b6a8f7ec2022-03-27T13:05:29ZHIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:fa647727-1d36-4cc1-a76c-f805b6a8f7ecEnglishSymplectic Elements at Oxford2005Drakesmith, HChen, NLedermann, HScreaton, GTownsend, AXu, XThe multifunctional Nef protein of HIV-1 is important for the progression to AIDS. One action of Nef is to down-regulate surface MHC I molecules, helping infected cells to evade immunity. We found that Nef also down-regulates the macrophage-expressed MHC 1b protein HFE, which regulates iron homeostasis and is mutated in the iron-overloading disorder hemochromatosis. In model cell lines, Nef reroutes HFE to a perinuclear structure that overlaps the trans-Golgi network, causing a 90% reduction of surface HFE. This activity requires a Src-kinase-binding proline-rich domain of Nef and a conserved tyrosine-based motif in the cytoplasmic tail of HFE. HIV-1 infection of ex vivo macrophages similarly down-regulates naturally expressed surface HFE in a Nef-dependent manner. The effect of Nef expression on cellular iron was explored; iron and ferritin accumulation were increased in HIV-1-infected ex vivo macrophages expressing wild-type HFE, but this effect was lost with Nef-deleted HIV-1 or when infecting macrophages from hemochromatosis patients expressing mutated HFE. The iron accumulation in HIV-1-infected HFE-expressing macrophages was paralleled by an increase in cellular HIV-1-gag expression. We conclude that, through Nef and HFE, HIV-1 directly regulates cellular iron metabolism, possibly benefiting viral growth. |
| spellingShingle | Drakesmith, H Chen, N Ledermann, H Screaton, G Townsend, A Xu, X HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis. |
| title | HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis. |
| title_full | HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis. |
| title_fullStr | HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis. |
| title_full_unstemmed | HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis. |
| title_short | HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis. |
| title_sort | hiv 1 nef down regulates the hemochromatosis protein hfe manipulating cellular iron homeostasis |
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