Structural basis of host protein hijacking in human T-cell leukemia virus integration

Veer Bhatt, Ke Shi, Daniel J. Salamango, Nicholas H. Moeller, Krishan K. Pandey, Sibes Bera, Thomas E. Bohl, Fredy Kurniawan, Kayo Orellana, Wei Zhang, Duane P. Grandgenett, Reuben S. Harris, Anna C. Sundborger-Lunna, Hideki Aihara

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number3121
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

Bibliographical note

Funding 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.

Publisher Copyright:
© 2020, The Author(s).

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