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....

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Autores principales:	Zaikun Xu, Robert Lodge, Christopher Power, Eric A. Cohen, Tom C. Hobman
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	HIV Vpu peroxisomes miRNAs β-catenin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/006b52600c4f4fdaae933574a259397e
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spelling	oai:doaj.org-article:006b52600c4f4fdaae933574a259397e2021-11-15T15:57:02ZThe HIV-1 Accessory Protein Vpu Downregulates Peroxisome Biogenesis10.1128/mBio.03395-192150-7511https://doaj.org/article/006b52600c4f4fdaae933574a259397e2020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03395-19https://doaj.org/toc/2150-7511ABSTRACT 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.Zaikun XuRobert LodgeChristopher PowerEric A. CohenTom C. HobmanAmerican Society for MicrobiologyarticleHIVVpuperoxisomesmiRNAsβ-cateninMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	HIV Vpu peroxisomes miRNAs β-catenin Microbiology QR1-502
spellingShingle	HIV Vpu peroxisomes miRNAs β-catenin Microbiology QR1-502 Zaikun Xu Robert Lodge Christopher Power Eric A. Cohen Tom C. Hobman The HIV-1 Accessory Protein Vpu Downregulates Peroxisome Biogenesis
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.
format	article
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
title	The HIV-1 Accessory Protein Vpu Downregulates Peroxisome Biogenesis
title_short	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_sort	hiv-1 accessory protein vpu downregulates peroxisome biogenesis
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/006b52600c4f4fdaae933574a259397e
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The HIV-1 Accessory Protein Vpu Downregulates Peroxisome Biogenesis

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