Department of Cell Biology, University of Alberta, Edmonton, Alberta, Canada.
Laboratory of Human Retrovirology, Institut de Recherches Cliniques de Montréal, Montréal, Quebec, Canada.
mBio. 2020 Mar 3;11(2):e03395-19. doi: 10.1128/mBio.03395-19.
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. 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.
人类免疫缺陷病毒 1 型（HIV-1）在人类中建立终身感染，这一过程依赖于其逃避宿主固有和适应性免疫防御的能力。最近，我们报道 HIV-1 感染导致细胞过氧化物酶体池的急剧减少。过氧化物酶体是代谢细胞器，在固有免疫反应中也作为信号平台发挥作用。在这里，我们表明 HIV-1 辅助蛋白 Vpu 是感染过程中细胞过氧化物酶体耗竭所必需和充分的。Vpu 诱导靶向编码过氧化物酶体形成和代谢功能所需蛋白的 mRNA 的四个 microRNA 的表达。发现 Vpu 下调过氧化物酶体的能力依赖于 Wnt/β-连环蛋白信号通路。鉴于过氧化物酶体在固有免疫信号和中枢神经系统功能中的重要性，Vpu 减弱抗病毒信号的作用似乎比以前认识到的更为多样化。最后，我们的研究结果强调了 Wnt/β-连环蛋白信号通路在通过调节生物发生因子的产生来维持过氧化物酶体稳态方面的潜在作用。HIV 感染者可能会经历加速衰老和神经紊乱的发展。最近，我们报道 HIV-1 感染导致巨噬细胞和脑组织中过氧化物酶体的大量丢失。这很重要，因为 (i) 过氧化物酶体对固有免疫反应很重要，以及 (ii) 过氧化物酶体功能的丧失与细胞衰老和神经退行性变有关。因此，了解 HIV-1 感染如何导致过氧化物酶体耗竭可能提供有关病毒如何建立持续性感染以及潜在神经紊乱发展的线索。在这里，我们表明辅助蛋白 Vpu 是诱导靶向过氧化物酶体生物发生因子的 microRNA 的必需和充分条件。Vpu 下调过氧化物酶体形成的能力取决于 Wnt/β-连环蛋白途径。因此，除了揭示 HIV-1 使用细胞内信号通路靶向抗病毒信号平台（过氧化物酶体）的新机制外，我们还发现了 Wnt/β-连环蛋白途径与过氧化物酶体稳态之间以前未知的联系。
