Integration of the reverse-transcribed viral DNA into host chromosomes is a critical step in the life-cycle of retroviruses, including an oncogenic delta(δ)-retrovirus human T-cell leukemia virus type-1 (HTLV-1). Retroviral integrase forms a higher order nucleoprotein assembly (intasome) to catalyze the integration reaction, in which the roles of host factors remain poorly understood. Here, we use cryo-electron microscopy to visualize the HTLV-1 intasome at 3.7-Å resolution. The structure together with functional analyses reveal that the B56γ (B’γ) subunit of an essential host enzyme, protein phosphatase 2 A (PP2A), is repurposed as an integral component of the intasome to mediate HTLV-1 integration. Our studies reveal a key host-virus interaction underlying the replication of an important human pathogen and highlight divergent integration strategies of retroviruses.
Bibliographical noteFunding Information:
We thank Dmitriy Mazurov for the HT1-M packaging vector and replication-dependent HTLV-1 and HIV-1 reporter vectors, Ewa Folta-Stogniew for SEC-MALS analysis, Surajit Banerjee for X-ray diffraction experiments, Takahide Kouno for preliminary negative stain EM, Brenda Watt and Gabriella Kiss for assistance with mass photometry, Nadine Shaban for discussions. The SEC-LS/UV/RI instrumentation in Biophysics Resource of Keck Facility at Yale University was supported by NIH Award 1S10RR023748-01 (to E.F.-S.). This work was supported by NIGMS R35-GM118047 (to H.A.), NIAID R37 AI064046 (to R.S.H.), the Hormel Foundation (to A.C.S.-L.), and NIAID K99 AI147811 (to D.J.S.). R.S.H. is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished University McKnight Professor, and an Investigator of the Howard Hughes Medical Institute.
© 2020, The Author(s).
- Cryoelectron Microscopy
- DNA, Viral/metabolism
- HEK293 Cells
- Host-Pathogen Interactions/genetics
- Human T-lymphotropic virus 1/enzymology
- Models, Molecular
- Point Mutation
- Protein Binding/genetics
- Protein Phosphatase 2/genetics
- Viral Proteins/metabolism
- Virus Integration/genetics
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Journal Article
- Research Support, N.I.H., Extramural