Back to Search
Start Over
Immunoproteasome activation enables human TRIM5α restriction of HIV-1.
- Source :
-
Nature microbiology [Nat Microbiol] 2019 Jun; Vol. 4 (6), pp. 933-940. Date of Electronic Publication: 2019 Mar 18. - Publication Year :
- 2019
-
Abstract
- Type 1 interferon suppresses viral replication by upregulating the expression of interferon-stimulated genes with diverse antiviral properties <superscript>1</superscript> . 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 <superscript>2-5</superscript> . 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 <superscript>6-8</superscript> . 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 <superscript>2,9,10</superscript> . 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 <superscript>11-13</superscript> , 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.
- Subjects :
- Antiviral Restriction Factors
Capsid drug effects
Capsid Proteins drug effects
Carrier Proteins genetics
Cell Line
Gene Silencing
HEK293 Cells
Humans
Interferon-alpha immunology
Interferon-alpha metabolism
Myxovirus Resistance Proteins genetics
Tripartite Motif Proteins
Ubiquitin-Protein Ligases
Virus Replication
Antiviral Agents antagonists & inhibitors
Carrier Proteins antagonists & inhibitors
Carrier Proteins immunology
Carrier Proteins metabolism
HIV Infections immunology
HIV-1 drug effects
Proteasome Endopeptidase Complex metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2058-5276
- Volume :
- 4
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Nature microbiology
- Publication Type :
- Academic Journal
- Accession number :
- 30886358
- Full Text :
- https://doi.org/10.1038/s41564-019-0402-0