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

doi:10.1038/s41467-020-16963-6

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 journal › Article › peer-review

28 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 language	English (US)
Article number	3121
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16963-6
State	Published - Jun 19 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).

Keywords

Cryoelectron Microscopy
DNA, Viral/metabolism
HEK293 Cells
Host-Pathogen Interactions/genetics
Human T-lymphotropic virus 1/enzymology
Humans
Integrases/metabolism
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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-16963-6

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Bhatt, V., Shi, K., Salamango, D. J., Moeller, N. H., Pandey, K. K., Bera, S., Bohl, T. E., Kurniawan, F., Orellana, K., Zhang, W., Grandgenett, D. P., Harris, R. S., Sundborger-Lunna, A. C., & Aihara, H. (2020). Structural basis of host protein hijacking in human T-cell leukemia virus integration. Nature communications, 11(1), Article 3121. https://doi.org/10.1038/s41467-020-16963-6

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title = "Structural basis of host protein hijacking in human T-cell leukemia virus integration",

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-{\AA} resolution. The structure together with functional analyses reveal that the B56γ (B{\textquoteright}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.",

keywords = "Cryoelectron Microscopy, DNA, Viral/metabolism, HEK293 Cells, Host-Pathogen Interactions/genetics, Human T-lymphotropic virus 1/enzymology, Humans, Integrases/metabolism, Models, Molecular, Point Mutation, Protein Binding/genetics, Protein Phosphatase 2/genetics, Viral Proteins/metabolism, Virus Integration/genetics",

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

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: {\textcopyright} 2020, The Author(s).",

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doi = "10.1038/s41467-020-16963-6",

language = "English (US)",

volume = "11",

journal = "Nature communications",

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T1 - Structural basis of host protein hijacking in human T-cell leukemia virus integration

AU - Bhatt, Veer

AU - Shi, Ke

AU - Salamango, Daniel J.

AU - Moeller, Nicholas H.

AU - Pandey, Krishan K.

AU - Bera, Sibes

AU - Bohl, Thomas E.

AU - Kurniawan, Fredy

AU - Orellana, Kayo

AU - Zhang, Wei

AU - Grandgenett, Duane P.

AU - Harris, Reuben S.

AU - Sundborger-Lunna, Anna C.

AU - Aihara, Hideki

N1 - 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).

PY - 2020/6/19

Y1 - 2020/6/19

N2 - 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.

AB - 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.

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KW - DNA, Viral/metabolism

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KW - Host-Pathogen Interactions/genetics

KW - Human T-lymphotropic virus 1/enzymology

KW - Humans

KW - Integrases/metabolism

KW - Models, Molecular

KW - Point Mutation

KW - Protein Binding/genetics

KW - Protein Phosphatase 2/genetics

KW - Viral Proteins/metabolism

KW - Virus Integration/genetics

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U2 - 10.1038/s41467-020-16963-6

DO - 10.1038/s41467-020-16963-6

M3 - Article

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SN - 2041-1723

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JO - Nature communications

JF - Nature communications

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ER -

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

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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