Multiple UBXM Family Members Inhibit Retrovirus and Lentivirus Production and Canonical NFkappaBeta Signaling by Stabilizing IkappaBalpha
Microbiology and Immunology
UBXN proteins likely participate in the global regulation of protein turnover, and we have shown that UBXN1 interferes with RIG-I-like receptor (RLR) signaling by interacting with MAVS and impeding its downstream effector functions. Here we demonstrate that over-expression of multiple UBXN family members decreased lentivirus and retrovirus production by several orders-of-magnitude in single cycle assays, at the level of long terminal repeat-driven transcription, and three family members, UBXN1, N9, and N11 blocked the canonical NFkappaB pathway by binding to Cullin1 (Cul1), inhibiting IkappaBalpha degradation. Multiple regions of UBXN1, including its UBA domain, were critical for its activity. Elimination of UBXN1 resulted in early murine embryonic lethality. shRNA-mediated knockdown of UBXN1 enhanced human immunodeficiency virus type 1 (HIV) production up to 10-fold in single cycle assays. In primary human fibroblasts, knockdown of UBXN1 caused prolonged degradation of IkappaBalpha and enhanced NFkappaB signaling, which was also observed after CRISPR-mediated knockout of UBXN1 in mouse embryo fibroblasts. Knockout of UBXN1 significantly up- and down-regulated hundreds of genes, notably those of several cell adhesion and immune signaling pathways. Reduction in UBXN1 gene expression in Jurkat T cells latently infected with HIV resulted in enhanced HIV gene expression, consistent with the role of UBXN1 in modulating the NFkappaB pathway. Based upon co-immunoprecipitation studies with host factors known to bind Cul1, models are presented as to how UBXN1 could be inhibiting Cul1 activity. The ability of UBXN1 and other family members to negatively regulate the NFkappaB pathway may be important for dampening the host immune response in disease processes and also re-activating quiescent HIV from latent viral reservoirs in chronically infected individuals.
Hu, Y., O'Boyle, K., Auer, J., Raju, S., You, F., Wang, P., Fikrig, E., & Sutton, R. (2017). Multiple UBXM Family Members Inhibit Retrovirus and Lentivirus Production and Canonical NFkappaBeta Signaling by Stabilizing IkappaBalpha. PLoS Pathogens, 13 (2), [Article] e1006187. https://doi.org/10.1371/journal.ppat.1006187