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; Heather O 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

Nat Commun. 2020 Jun 19;11(1):3121. doi: 10.1038/s41467-020-16963-6.

Authors

Veer Bhatt^#^{1

2}, Ke Shi^#^{2

3

4}, Daniel J Salamango^#^{2

3

4}, Nicholas H Moeller^{2

3

4}, Krishan K Pandey⁵, Sibes Bera⁵, Heather O Bohl^{2

3

4}, Fredy Kurniawan^{2

3

4}, Kayo Orellana^{2

3

4}, Wei Zhang^{2

4

6

7}, Duane P Grandgenett⁵, Reuben S Harris^{2

3

4

8}, Anna C Sundborger-Lunna^{9

10}, Hideki Aihara^{11

12

13}

Affiliations

¹ The Hormel Institute, University of Minnesota, 801 16th Avenue N.E., Austin, MN, 55912, USA.
² Masonic Cancer Center, University of Minnesota, 2231 6th Street S.E., Minneapolis, MN, 55455, USA.
³ Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 321 Church Street S.E., Minneapolis, MN, 55455, USA.
⁴ Institute for Molecular Virology, University of Minnesota, 515 Delaware Street S.E., Minneapolis, MN, 55455, USA.
⁵ Department of Molecular Microbiology and Immunology, Saint Louis University, 1100 S. Grand Boulevard, St. Louis, MO, 63104, USA.
⁶ Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, 515 Delaware Street S.E., Minneapolis, MN, 55455, USA.
⁷ Characterization Facility, College of Science and Engineering, University of Minnesota, 100 Union Street S.E., Minneapolis, MN, 55455, USA.
⁸ Howard Hughes Medical Institute, University of Minnesota, 2231 6th Street S.E., Minneapolis, MN, 55455, USA.
⁹ The Hormel Institute, University of Minnesota, 801 16th Avenue N.E., Austin, MN, 55912, USA. asundbor@umn.edu.
¹⁰ Masonic Cancer Center, University of Minnesota, 2231 6th Street S.E., Minneapolis, MN, 55455, USA. asundbor@umn.edu.
¹¹ Masonic Cancer Center, University of Minnesota, 2231 6th Street S.E., Minneapolis, MN, 55455, USA. aihar001@umn.edu.
¹² Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 321 Church Street S.E., Minneapolis, MN, 55455, USA. aihar001@umn.edu.
¹³ Institute for Molecular Virology, University of Minnesota, 515 Delaware Street S.E., Minneapolis, MN, 55455, USA. aihar001@umn.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

DNA, Viral
Viral Proteins
Integrases
PPP2R5C protein, human
Protein Phosphatase 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding