The role of RhoA signaling pathways in regulating HIV-1 replication Public Deposited

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  • March 21, 2019
  • Loomis, Rebecca Jo
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
  • RhoGTPases are involved in regulating important cellular processes including cytoskeletal organization, gene transcription and membrane vesicle transport – poising RhoGTPases to link these pathways to HIV-1 replication. However, RhoGTPase function in HIV-1 replication is essentially unknown. RhoA activation can be modulated by the cytoplasmic tail of the HIV-1 transmembrane envelope glycoprotein through its interaction with p115RhoGEF, a RhoA specific activator. Furthermore, activation of the RhoA signaling pathway inhibits HIV-1 gene expression. To investigate how RhoA pathways modulate HIV-1 replication, I tested individual RhoA effectors. Rho-associated kinase (ROCK) specifically inhibits HIV-1 gene expression in T cells. A ROCK specific inhibitor counteracts RhoA inhibition of HIV-1 gene expression, indicating that RhoA signals via ROCK to inhibit HIV-1. HIV-1 LTR mutations in either the NF-κB or Sp1 binding sites abrogate ROCK-mediated inhibition. ROCK may disrupt the cooperative interaction between NF-κB and Sp1 or modulate epigenetic regulation to inhibit HIV-1 gene expression. Additionally, I identified a disparate role for the RhoA effector, citron kinase. Citron kinase preferentially enhances HIV-1 virion production by promoting exocytosis. This activity depends on the leucine zipper, Rho-binding and zinc-finger domains, but not the kinase activity, of citron kinase. Although citron kinase-mediated enhancement of HIV-1 replication is late domain independent, an intact late endosomal sorting pathway is required. Citron kinase may act as a scaffold, linking host proteins to the endosomal sorting and exosomal pathways. I also found a functional interaction between citron kinase and the ESCRT-I component, Tsg101. Ectopic expression of either citron kinase or Tsg101 enhances HIV-1 virion production, however, coexpression of citron kinase and Tsg101 inhibits HIV-1 replication. This functional interaction is mediated by the kinase activity of citron and the PTAP-binding region of Tsg101. The two activities of citron kinase involved in HIV-1 regulation are distinct and independent of one another. In summary, I identified two RhoA effectors, ROCK and citron kinase to regulate HIV-1 replication. ROCK specifically inhibits HIV-1 gene expression while citron kinase demonstrates a disparate role. These RhoA effectors may provide novel targets for developing antiviral therapeutics and further our understanding of the role of RhoA signaling pathways in HIV-1 replication.
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  • Su, Lishan
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  • University of North Carolina at Chapel Hill
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