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Immunoproteasome activation enables human TRIM5α restriction of HIV-1
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Journal Article
Immunoproteasome activation enables human TRIM5α restriction of HIV-1
2019
Overview
Type 1 interferon suppresses viral replication by upregulating the expression of interferon-stimulated genes with diverse antiviral properties
1
. 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 susceptible
2
–
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 effect
6
–
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 TRIM5α
2
,
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 complex
11
–
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.
Using a small interfering RNA-based library screening in interferon-treated cells, the authors identified human tripartite-containing motif 5α as potent restriction factor that inhibits HIV-1 DNA synthesis and infection in a capsid- and immunoproteasome-dependent manner.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/1
/ 13/106
/ 13/109
/ 13/44
/ 13/89
/ 38/70
/ 38/77
/ 82/29
/ 82/80
/ Antiviral Agents - antagonists & inhibitors
/ Antiviral Restriction Factors
/ Biomedical and Life Sciences
/ Capsid Proteins - drug effects
/ Capsids
/ Carrier Proteins - antagonists & inhibitors
/ Carrier Proteins - immunology
/ Carrier Proteins - metabolism
/ DNA
/ HIV
/ Human immunodeficiency virus
/ Humans
/ Interferon-alpha - immunology
/ Interferon-alpha - metabolism
/ Letter
/ Myxovirus Resistance Proteins - genetics
/ Proteasome Endopeptidase Complex - metabolism
/ siRNA
/ Virology
