The HIV-1 Accessory Protein Vpu Downregulates Peroxisome Biogenesis
ABSTRACT Human immunodeficiency virus type 1 (HIV-1) establishes lifelong infections in humans, a process that relies on its ability to thwart innate and adaptive immune defenses of the host. Recently, we reported that HIV-1 infection results in a dramatic reduction of the cellular peroxisome pool....
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2020-04-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.03395-19 |
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| author | Zaikun Xu Robert Lodge Christopher Power Eric A. Cohen Tom C. Hobman |
| author_facet | Zaikun Xu Robert Lodge Christopher Power Eric A. Cohen Tom C. Hobman |
| author_sort | Zaikun Xu |
| collection | DOAJ |
| description | ABSTRACT Human immunodeficiency virus type 1 (HIV-1) establishes lifelong infections in humans, a process that relies on its ability to thwart innate and adaptive immune defenses of the host. Recently, we reported that HIV-1 infection results in a dramatic reduction of the cellular peroxisome pool. Peroxisomes are metabolic organelles that also function as signaling platforms in the innate immune response. Here, we show that the HIV-1 accessory protein Vpu is necessary and sufficient for the depletion of cellular peroxisomes during infection. Vpu induces the expression of four microRNAs that target mRNAs encoding proteins required for peroxisome formation and metabolic function. The ability of Vpu to downregulate peroxisomes was found to be dependent upon the Wnt/β-catenin signaling pathway. Given the importance of peroxisomes in innate immune signaling and central nervous system function, the roles of Vpu in dampening antiviral signaling appear to be more diverse than previously realized. Finally, our findings highlight a potential role for Wnt/β-catenin signaling in peroxisome homeostasis through modulating the production of biogenesis factors. IMPORTANCE People living with HIV can experience accelerated aging and the development of neurological disorders. Recently, we reported that HIV-1 infection results in a dramatic loss of peroxisomes in macrophages and brain tissue. This is significant because (i) peroxisomes are important for the innate immune response and (ii) loss of peroxisome function is associated with cellular aging and neurodegeneration. Accordingly, understanding how HIV-1 infection causes peroxisome depletion may provide clues regarding how the virus establishes persistent infections and, potentially, the development of neurological disorders. Here, we show that the accessory protein Vpu is necessary and sufficient for the induction of microRNAs that target peroxisome biogenesis factors. The ability of Vpu to downregulate peroxisome formation depends on the Wnt/β-catenin pathway. Thus, in addition to revealing a novel mechanism by which HIV-1 uses intracellular signaling pathways to target antiviral signaling platforms (peroxisomes), we have uncovered a previously unknown link between the Wnt/β-catenin pathway and peroxisome homeostasis. |
| first_indexed | 2024-12-14T16:38:24Z |
| format | Article |
| id | doaj.art-006b52600c4f4fdaae933574a259397e |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-14T16:38:24Z |
| publishDate | 2020-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-006b52600c4f4fdaae933574a259397e2022-12-21T22:54:24ZengAmerican Society for MicrobiologymBio2150-75112020-04-0111210.1128/mBio.03395-19The HIV-1 Accessory Protein Vpu Downregulates Peroxisome BiogenesisZaikun Xu0Robert Lodge1Christopher Power2Eric A. Cohen3Tom C. Hobman4Department of Cell Biology, University of Alberta, Edmonton, Alberta, CanadaLaboratory of Human Retrovirology, Institut de Recherches Cliniques de Montréal, Montréal, Quebec, CanadaDepartment of Medicine, University of Alberta, Edmonton, Alberta, CanadaLaboratory of Human Retrovirology, Institut de Recherches Cliniques de Montréal, Montréal, Quebec, CanadaDepartment of Cell Biology, University of Alberta, Edmonton, Alberta, CanadaABSTRACT Human immunodeficiency virus type 1 (HIV-1) establishes lifelong infections in humans, a process that relies on its ability to thwart innate and adaptive immune defenses of the host. Recently, we reported that HIV-1 infection results in a dramatic reduction of the cellular peroxisome pool. Peroxisomes are metabolic organelles that also function as signaling platforms in the innate immune response. Here, we show that the HIV-1 accessory protein Vpu is necessary and sufficient for the depletion of cellular peroxisomes during infection. Vpu induces the expression of four microRNAs that target mRNAs encoding proteins required for peroxisome formation and metabolic function. The ability of Vpu to downregulate peroxisomes was found to be dependent upon the Wnt/β-catenin signaling pathway. Given the importance of peroxisomes in innate immune signaling and central nervous system function, the roles of Vpu in dampening antiviral signaling appear to be more diverse than previously realized. Finally, our findings highlight a potential role for Wnt/β-catenin signaling in peroxisome homeostasis through modulating the production of biogenesis factors. IMPORTANCE People living with HIV can experience accelerated aging and the development of neurological disorders. Recently, we reported that HIV-1 infection results in a dramatic loss of peroxisomes in macrophages and brain tissue. This is significant because (i) peroxisomes are important for the innate immune response and (ii) loss of peroxisome function is associated with cellular aging and neurodegeneration. Accordingly, understanding how HIV-1 infection causes peroxisome depletion may provide clues regarding how the virus establishes persistent infections and, potentially, the development of neurological disorders. Here, we show that the accessory protein Vpu is necessary and sufficient for the induction of microRNAs that target peroxisome biogenesis factors. The ability of Vpu to downregulate peroxisome formation depends on the Wnt/β-catenin pathway. Thus, in addition to revealing a novel mechanism by which HIV-1 uses intracellular signaling pathways to target antiviral signaling platforms (peroxisomes), we have uncovered a previously unknown link between the Wnt/β-catenin pathway and peroxisome homeostasis.https://journals.asm.org/doi/10.1128/mBio.03395-19HIVVpuperoxisomesmiRNAsβ-catenin |
| spellingShingle | Zaikun Xu Robert Lodge Christopher Power Eric A. Cohen Tom C. Hobman The HIV-1 Accessory Protein Vpu Downregulates Peroxisome Biogenesis mBio HIV Vpu peroxisomes miRNAs β-catenin |
| title | The HIV-1 Accessory Protein Vpu Downregulates Peroxisome Biogenesis |
| title_full | The HIV-1 Accessory Protein Vpu Downregulates Peroxisome Biogenesis |
| title_fullStr | The HIV-1 Accessory Protein Vpu Downregulates Peroxisome Biogenesis |
| title_full_unstemmed | The HIV-1 Accessory Protein Vpu Downregulates Peroxisome Biogenesis |
| title_short | The HIV-1 Accessory Protein Vpu Downregulates Peroxisome Biogenesis |
| title_sort | hiv 1 accessory protein vpu downregulates peroxisome biogenesis |
| topic | HIV Vpu peroxisomes miRNAs β-catenin |
| url | https://journals.asm.org/doi/10.1128/mBio.03395-19 |
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