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Truncated CPSF6 Forms Higher-Order Complexes That Bind and Disrupt HIV-1 Capsid
Jiying Ning1,2, Zhou Zhong2,3, Douglas K Fischer2,3
1Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Journal of Virology
|April 13, 2018
Summary
Truncated CPSF6 protein forms oligomers that disrupt HIV-1 capsid, inhibiting viral infection by causing premature uncoating. This study reveals the molecular mechanism of CPSF6-358
Area of Science:
- Virology
- Molecular Biology
- Structural Biology
Background:
- Cleavage and polyadenylation specificity factor 6 (CPSF6) interacts with HIV-1 capsid, influencing viral nuclear transport.
- Truncated CPSF6 (CPSF6-358) inhibits HIV-1 infection by targeting the capsid and blocking nuclear entry.
Purpose of the Study:
- To elucidate the molecular mechanism by which CPSF6-358 restricts HIV-1 infection.
- To characterize the interaction between CPSF6-358 and the HIV-1 capsid.
Main Methods:
- In vitro biochemical assays and transmission electron microscopy.
- In vivo fixed- and live-cell imaging.
- Analysis of wild-type and mutant HIV-1 capsid proteins.
Main Results:
- Purified CPSF6-358 forms oligomers that bind to wild-type HIV-1 capsid but not to mutant capsid.
- CPSF6-358 oligomers disrupt assembled HIV-1 capsid tubes.
- CPSF6-358 forms cytoplasmic puncta upon infection and causes capsid permeabilization, dependent on CPSF6 binding.
- These events are blocked by a small-molecule inhibitor of CPSF6-358 binding.
Conclusions:
- CPSF6-358 exists as oligomers that directly interact with and disrupt the HIV-1 capsid.
- This disruption leads to premature capsid uncoating, a mechanism detrimental to HIV-1 replication.
- The study provides direct evidence for the oligomeric nature of CPSF6-358 and its role in restricting HIV-1 infection.
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