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HIV-1 promotes ubiquitination of the amyloidogenic C-terminal fragment of APP to support viral replication

Author

Listed:
  • Feng Gu

    (Northwestern University Feinberg School of Medicine)

  • Marie Boisjoli

    (Northwestern University Feinberg School of Medicine)

  • Mojgan H. Naghavi

    (Northwestern University Feinberg School of Medicine)

Abstract

HIV-1 replication in macrophages and microglia involves intracellular assembly and budding into modified subsets of multivesicular bodies (MVBs), which support both viral persistence and spread. However, the cellular factors that regulate HIV-1’s vesicular replication remain poorly understood. Recently, amyloid precursor protein (APP) was identified as an inhibitor of HIV-1 replication in macrophages and microglia via an unknown mechanism. Here, we show that entry of HIV-1 Gag into MVBs is blocked by the amyloidogenic C-terminal fragment of APP, “C99”, but not by the non-amyloidogenic product, “C83”. To counter this, Gag promotes multi-site ubiquitination of C99 which controls both exocytic sorting of MVBs and further processing of C99 into toxic amyloids. Processing of C99, entry of Gag into MVBs and release of infectious virus could be suppressed by expressing ubiquitination-defective C99 or by γ-secretase inhibitor treatment, suggesting that APP’s amyloidogenic pathway functions to sense and suppress HIV-1 replication in macrophages and microglia.

Suggested Citation

  • Feng Gu & Marie Boisjoli & Mojgan H. Naghavi, 2023. "HIV-1 promotes ubiquitination of the amyloidogenic C-terminal fragment of APP to support viral replication," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40000-x
    DOI: 10.1038/s41467-023-40000-x
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    References listed on IDEAS

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    2. Qingqing Chai & Vladimir Jovasevic & Viacheslav Malikov & Yosef Sabo & Scott Morham & Derek Walsh & Mojgan H. Naghavi, 2017. "HIV-1 counteracts an innate restriction by amyloid precursor protein resulting in neurodegeneration," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    3. Etienne Morel & Zeina Chamoun & Zofia M. Lasiecka & Robin B. Chan & Rebecca L. Williamson & Christopher Vetanovetz & Claudia Dall’Armi & Sabrina Simoes & Kimberly S. Point Du Jour & Brian D. McCabe & , 2013. "Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system," Nature Communications, Nature, vol. 4(1), pages 1-13, October.
    4. Viacheslav Malikov & Eveline Santos da Silva & Vladimir Jovasevic & Geoffrey Bennett & Daniel A. de Souza Aranha Vieira & Bianca Schulte & Felipe Diaz-Griffero & Derek Walsh & Mojgan H. Naghavi, 2015. "HIV-1 capsids bind and exploit the kinesin-1 adaptor FEZ1 for inward movement to the nucleus," Nature Communications, Nature, vol. 6(1), pages 1-13, May.
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