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Jiménez-Guardeño, José Manuel Apolonia, Luis Betancor, Gilberto Malim, Michael H. 2024-09-28T17:37:48Z 2024-09-28T17:37:48Z 2019 Jimenez-Guardeño, J.M., Apolonia, L., Betancor, G. et al. Immunoproteasome activation enables human TRIM5α restriction of HIV-1. Nat Microbiol 4, 933–940 (2019). https://doi.org/10.1038/s41564-019-0402-0 https://hdl.handle.net/10630/33866 10.1038/s41564-019-0402-0 Type 1 interferon suppresses viral replication by upregulating the expression of interferon-stimulated genes with diverse antiviral properties1. The replication of human immunodeficiency virus type 1 (HIV-1) is naturally inhibited by interferon, with the steps between viral entry and chromosomal integration of viral DNA being notably susceptible2-5. The interferon-stimulated gene myxovirus resistance 2 has been defined as an effective postentry inhibitor of HIV-1, but is only partially responsible for interferon's suppressive effect6-8. Using small interfering RNA-based library screening in interferon-α-treated cells, we sought to characterize further interferon-stimulated genes that target the pre-integration phases of HIV-1 infection, and identified human tripartite-containing motif 5α (TRIM5α) as a potent anti-HIV-1 restriction factor. Human TRIM5α, in contrast with many nonhuman orthologues, has not generally been ascribed substantial HIV-1 inhibitory function, a finding attributed to ineffective recognition of cytoplasmic viral capsids by TRIM5α2,9,10. Here, we demonstrate that interferon-α-mediated stimulation of the immunoproteasome, a proteasome isoform mainly present in immune cells and distinguished from the constitutive proteasome by virtue of its different catalytic β-subunits, as well as the proteasome activator 28 regulatory complex11-13, and the associated accelerated turnover of TRIM5α underpin the reprogramming of human TRIM5α for effective capsid-dependent inhibition of HIV-1 DNA synthesis and infection. These observations identify a mechanism for regulating human TRIM5α antiviral function in human cells and rationalize how TRIM5α participates in the immune control of HIV-1 infection. eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Virología Immunoproteasome activation enables human TRIM5α restriction of HIV-1 journal article