Immunoproteasome activation enables human TRIM5? restriction of HIV-1.

ABSTRACT: 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-?-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 5? (TRIM5?) as a potent anti-HIV-1 restriction factor. Human TRIM5?, 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 TRIM5?2,9,10. Here, we demonstrate that interferon-?-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 ?-subunits, as well as the proteasome activator 28 regulatory complex11-13, and the associated accelerated turnover of TRIM5? underpin the reprogramming of human TRIM5? for effective capsid-dependent inhibition of HIV-1 DNA synthesis and infection. These observations identify a mechanism for regulating human TRIM5? antiviral function in human cells and rationalize how TRIM5? participates in the immune control of HIV-1 infection.

SUBMITTER: Jimenez-Guardeno JM 

PROVIDER: S-EPMC6544544 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature