DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Structural Mimicry Drives HIV-1 Rev-Mediated HERV-K Expression

Abstract

Expression of the Human Endogenous Retrovirus Type K (HERV-K), the youngest and most active HERV, has been associated with various cancers and neurodegenerative diseases. As in all retroviruses, a fraction of HERV-K transcripts is exported from the nucleus in unspliced or incompletely spliced forms to serve as templates for translation of viral proteins. In a fraction of HERV-K loci (Type 2 proviruses), nuclear export of the unspliced HERV-K mRNA appears to be mediated by a cis-acting signal on the mRNA, the RcRE, and the protein Rec—these are analogous to the RRE-Rev system in HIV-1. Interestingly, the HIV-1 Rev protein is able to mediate the nuclear export of the HERV-K RcRE, contributing to elevated HERV-K expression in HIV-infected patients. We aimed to understand the structural basis for HIV Rev-HERV-K RcRE recognition. We examined the conformation of the RcRE RNA in solution using small-angle X-ray scattering (SAXS) and atomic force microscopy (AFM). We found that the 433-nt long RcRE can assume folded or extended conformations as observed by AFM. SAXS analysis of a truncated RcRE variant revealed an “A”-shaped topological structure similar to the one previously reported for the HIV-1 RRE. The effect of the overall topology was examined using several deletionmore » variants. SAXS and biochemical analyses demonstrated that the “A” shape is necessary for efficient Rev-RcRE complex formation in vitro and nuclear export activity in cell culture. Here, the findings provide insight into the mechanism of HERV-K expression and a structural explanation for HIV-1 Rev-mediated expression of HERV-K in HIV-infected patients.« less

Authors:
 [1];  [2];  [3];  [4];  [1];  [1];  [1];  [3];  [1];  [3];  [3]
  1. United States Naval Academy, Annapolis, MD (United States)
  2. SAXS Core Facility of the National Cancer Institute, Frederick, MD (United States)
  3. National Inst. of Health, Frederick, MD (United States)
  4. United States Naval Academy, Annapolis, MD (United States); Stanford School of Medicine, Stanford, CA (United States)
Publication Date:
Research Org.:
United States Naval Academy, Annapolis, MD (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH)
OSTI Identifier:
1713061
Alternate Identifier(s):
OSTI ID: 1775965
Grant/Contract Number:  
AC02-06CH11357; HHSN26120080001E
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Molecular Biology
Additional Journal Information:
Journal Volume: 432; Journal Issue: 24; Related Information: Ina P. O'Carroll, Lixin Fan, Tomas Kroupa, Erin K. McShane, Christophe Theodore, Elizabeth A. Yates, Benjamin Kondrup, Jienyu Ding, Tyler S. Martin, Alan Rein, Yun-Xing Wang,Structural mimicry drives HIV-1 Rev-mediated HERV-K expression,Journal of Molecular Biology, 2020. https://doi.org/10.1016/j.jmb.2020.11.010.; Journal ID: ISSN 0022-2836
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; HERV-K; RcRE; small-angle X-ray scattering; atomic force microscopy; HIV-1 Rev

Citation Formats

O'Carroll, Ina P., Fan, Lixin, Kroupa, Tomáš, McShane, Erin K., Theodore, Christophe, Yates, Elizabeth A., Kondrup, Benjamin, Ding, Jienyu, Martin, Tyler S., Rein, Alan, and Wang, Yun-Xing. Structural Mimicry Drives HIV-1 Rev-Mediated HERV-K Expression. United States: N. p., 2020. Web. doi:10.1016/j.jmb.2020.11.010.
O'Carroll, Ina P., Fan, Lixin, Kroupa, Tomáš, McShane, Erin K., Theodore, Christophe, Yates, Elizabeth A., Kondrup, Benjamin, Ding, Jienyu, Martin, Tyler S., Rein, Alan, & Wang, Yun-Xing. Structural Mimicry Drives HIV-1 Rev-Mediated HERV-K Expression. United States. https://doi.org/10.1016/j.jmb.2020.11.010
O'Carroll, Ina P., Fan, Lixin, Kroupa, Tomáš, McShane, Erin K., Theodore, Christophe, Yates, Elizabeth A., Kondrup, Benjamin, Ding, Jienyu, Martin, Tyler S., Rein, Alan, and Wang, Yun-Xing. Sat . "Structural Mimicry Drives HIV-1 Rev-Mediated HERV-K Expression". United States. https://doi.org/10.1016/j.jmb.2020.11.010. https://www.osti.gov/servlets/purl/1713061.
@article{osti_1713061,
title = {Structural Mimicry Drives HIV-1 Rev-Mediated HERV-K Expression},
author = {O'Carroll, Ina P. and Fan, Lixin and Kroupa, Tomáš and McShane, Erin K. and Theodore, Christophe and Yates, Elizabeth A. and Kondrup, Benjamin and Ding, Jienyu and Martin, Tyler S. and Rein, Alan and Wang, Yun-Xing},
abstractNote = {Expression of the Human Endogenous Retrovirus Type K (HERV-K), the youngest and most active HERV, has been associated with various cancers and neurodegenerative diseases. As in all retroviruses, a fraction of HERV-K transcripts is exported from the nucleus in unspliced or incompletely spliced forms to serve as templates for translation of viral proteins. In a fraction of HERV-K loci (Type 2 proviruses), nuclear export of the unspliced HERV-K mRNA appears to be mediated by a cis-acting signal on the mRNA, the RcRE, and the protein Rec—these are analogous to the RRE-Rev system in HIV-1. Interestingly, the HIV-1 Rev protein is able to mediate the nuclear export of the HERV-K RcRE, contributing to elevated HERV-K expression in HIV-infected patients. We aimed to understand the structural basis for HIV Rev-HERV-K RcRE recognition. We examined the conformation of the RcRE RNA in solution using small-angle X-ray scattering (SAXS) and atomic force microscopy (AFM). We found that the 433-nt long RcRE can assume folded or extended conformations as observed by AFM. SAXS analysis of a truncated RcRE variant revealed an “A”-shaped topological structure similar to the one previously reported for the HIV-1 RRE. The effect of the overall topology was examined using several deletion variants. SAXS and biochemical analyses demonstrated that the “A” shape is necessary for efficient Rev-RcRE complex formation in vitro and nuclear export activity in cell culture. Here, the findings provide insight into the mechanism of HERV-K expression and a structural explanation for HIV-1 Rev-mediated expression of HERV-K in HIV-infected patients.},
doi = {10.1016/j.jmb.2020.11.010},
journal = {Journal of Molecular Biology},
number = 24,
volume = 432,
place = {United States},
year = {Sat Nov 14 00:00:00 EST 2020},
month = {Sat Nov 14 00:00:00 EST 2020}
}

Works referenced in this record:

Long-term reinfection of the human genome by endogenous retroviruses
journal, March 2004

  • Belshaw, R.; Pereira, V.; Katzourakis, A.
  • Proceedings of the National Academy of Sciences, Vol. 101, Issue 14
  • DOI: 10.1073/pnas.0307800101

Initial sequencing and analysis of the human genome
journal, February 2001

  • Lander, Eric S.; Linton, Lauren M.
  • Nature, Vol. 409, Issue 6822, p. 860-921
  • DOI: 10.1038/35057062

From ancestral infectious retroviruses to bona fide cellular genes: Role of the captured syncytins in placentation
journal, September 2012


Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells
journal, April 2015

  • Grow, Edward J.; Flynn, Ryan A.; Chavez, Shawn L.
  • Nature, Vol. 522, Issue 7555
  • DOI: 10.1038/nature14308

Detection of the human endogenous retrovirus ERV3-encoded Env-protein in human tissues using antibody-based proteomics
journal, November 2013

  • Fei, Chen; Atterby, Christina; Edqvist, Per-Henrik
  • Journal of the Royal Society of Medicine, Vol. 107, Issue 1
  • DOI: 10.1177/0141076813509981

Genetic Evidence That Captured Retroviral Envelope syncytins Contribute to Myoblast Fusion and Muscle Sexual Dimorphism in Mice
journal, September 2016


Human endogenous retrovirus-K (HML-2): a comprehensive review
journal, October 2018

  • Garcia-Montojo, Marta; Doucet-O’Hare, Tara; Henderson, Lisa
  • Critical Reviews in Microbiology, Vol. 44, Issue 6
  • DOI: 10.1080/1040841X.2018.1501345

Human Endogenous Retroviruses Are Ancient Acquired Elements Still Shaping Innate Immune Responses
journal, September 2018


Human Endogenous Retroviruses in Neurological Diseases
journal, April 2018


The viruses in all of us: characteristics and biological significance of human endogenous retrovirus sequences.
journal, May 1996

  • Lower, R.; Lower, J.; Kurth, R.
  • Proceedings of the National Academy of Sciences, Vol. 93, Issue 11
  • DOI: 10.1073/pnas.93.11.5177

Human Endogenous Retroviruses in Health and Disease: A Symbiotic Perspective
journal, December 2004


Origins and evolutionary consequences of ancient endogenous retroviruses
journal, April 2019


Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses
journal, January 2011

  • Subramanian, Ravi P.; Wildschutte, Julia H.; Russo, Crystal
  • Retrovirology, Vol. 8, Issue 1
  • DOI: 10.1186/1742-4690-8-90

Genomic impact, chromosomal distribution and transcriptional regulation of HERV elements
journal, May 2012


Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K–Related Sequences
journal, April 2015

  • Contreras-Galindo, Rafael; Kaplan, Mark H.; Dube, Derek
  • Journal of Virology, Vol. 89, Issue 14
  • DOI: 10.1128/JVI.00544-15

The Neuronal Gene Arc Encodes a Repurposed Retrotransposon Gag Protein that Mediates Intercellular RNA Transfer
journal, January 2018


Intron retention in viruses and cellular genes: Detention, border controls and passports
journal, March 2018

  • Rekosh, David; Hammarskjold, Marie-Louise
  • Wiley Interdisciplinary Reviews: RNA, Vol. 9, Issue 3
  • DOI: 10.1002/wrna.1470

Viral Evasion and Manipulation of Host RNA Quality Control Pathways
journal, May 2016


Transcriptional and Posttranscriptional Regulation of HIV-1 Gene Expression
journal, November 2011


Characterisation of the passive permeability barrier of nuclear pore complexes
journal, August 2009

  • Mohr, Dagmar; Frey, Steffen; Fischer, Torsten
  • The EMBO Journal, Vol. 28, Issue 17
  • DOI: 10.1038/emboj.2009.200

The type I human T-cell leukemia virus (HTLV-I) Rex trans-activator binds directly to the HTLV-I Rex and the type 1 human immunodeficiency virus Rev RNA response elements.
journal, July 1991

  • Bogerd, H. P.; Huckaby, G. L.; Ahmed, Y. F.
  • Proceedings of the National Academy of Sciences, Vol. 88, Issue 13
  • DOI: 10.1073/pnas.88.13.5704

Identification and Mutational Analysis of a Rej Response Element in Jaagsiekte Sheep Retrovirus RNA
journal, September 2009

  • Nitta, Takayuki; Hofacre, Andrew; Hull, Stacey
  • Journal of Virology, Vol. 83, Issue 23
  • DOI: 10.1128/JVI.01754-08

Binding of Equine Infectious Anemia Virus Rev to an Exon Splicing Enhancer Mediates Alternative Splicing and Nuclear Export of Viral mRNAs
journal, May 2000


Identification of the Rem-responsive element of mouse mammary tumor virus
journal, September 2008

  • Mullner, M.; Salmons, B.; Gunzburg, W. H.
  • Nucleic Acids Research, Vol. 36, Issue 19
  • DOI: 10.1093/nar/gkn608

Mouse Mammary Tumor Virus Encodes a Self-Regulatory RNA Export Protein and Is a Complex Retrovirus
journal, December 2005


The human endogenous retrovirus K Rev response element coincides with a predicted RNA folding region
journal, November 2000


Identification of a Rev-related protein by analysis of spliced transcripts of the human endogenous retroviruses HTDV/HERV-K.
journal, January 1995


An ancient family of human endogenous retroviruses encodes a functional homolog of the HIV-1 Rev protein
journal, November 1999

  • Yang, J.; Bogerd, H. P.; Peng, S.
  • Proceedings of the National Academy of Sciences, Vol. 96, Issue 23
  • DOI: 10.1073/pnas.96.23.13404

cORF and RcRE, the Rev/Rex and RRE/RxRE Homologues of the Human Endogenous Retrovirus Family HTDV/HERV-K
journal, November 1999


HIV-1 Rev interacts with HERV-K RcREs present in the human genome and promotes export of unspliced HERV-K proviral RNA
journal, December 2019


A Molecular Rheostat
journal, August 1994

  • Mann, Derek A.; Mikaélian, Ivan; Zemmel, Rodney W.
  • Journal of Molecular Biology, Vol. 241, Issue 2
  • DOI: 10.1006/jmbi.1994.1488

The HIV-1 Rev response element (RRE) adopts alternative conformations that promote different rates of virus replication
journal, April 2015

  • Sherpa, Chringma; Rausch, Jason W.; Le Grice, Stuart F. J.
  • Nucleic Acids Research, Vol. 43, Issue 9
  • DOI: 10.1093/nar/gkv313

Architecture and secondary structure of an entire HIV-1 RNA genome
journal, August 2009

  • Watts, Joseph M.; Dang, Kristen K.; Gorelick, Robert J.
  • Nature, Vol. 460, Issue 7256
  • DOI: 10.1038/nature08237

Biochemical Analysis of the Complex between the Tetrameric Export Adapter Protein Rec of HERV-K/HML-2 and the Responsive RNA Element RcRE pck30
journal, June 2012

  • Langner, J. S.; Fuchs, N. V.; Hoffmann, J.
  • Journal of Virology, Vol. 86, Issue 17
  • DOI: 10.1128/JVI.00121-12

An Unusual Topological Structure of the HIV-1 Rev Response Element
journal, October 2013


Expression of HERV-K108 envelope interferes with HIV-1 production
journal, September 2017


Structural analysis of intrinsically disordered proteins by small-angle X-ray scattering
journal, January 2012

  • Bernadó, Pau; Svergun, Dmitri I.
  • Mol. BioSyst., Vol. 8, Issue 1
  • DOI: 10.1039/C1MB05275F

Small-angle X-ray scattering: a bridge between RNA secondary structures and three-dimensional topological structures
journal, February 2015

  • Fang, Xianyang; Stagno, Jason R.; Bhandari, Yuba R.
  • Current Opinion in Structural Biology, Vol. 30
  • DOI: 10.1016/j.sbi.2015.02.010

Accurate assessment of mass, models and resolution by small-angle scattering
journal, April 2013


A Method for Helical RNA Global Structure Determination in Solution Using Small-Angle X-Ray Scattering and NMR Measurements
journal, October 2009


A new method for the evaluation of small-angle scattering data
journal, October 1977


Small-angle scattering studies of biological macromolecules in solution
journal, September 2003


Changes in Biomolecular Conformation Seen by Small Angle X-ray Scattering
journal, June 2001


Characterizing flexible and intrinsically unstructured biological macromolecules by SAS using the Porod-Debye law
journal, April 2011

  • Rambo, Robert P.; Tainer, John A.
  • Biopolymers, Vol. 95, Issue 8
  • DOI: 10.1002/bip.21638

RNA-guided assembly of Rev-RRE nuclear export complexes
journal, August 2014


Structure of the HIV-1 Rev response element alone and in complex with regulator of virion (Rev) studied by atomic force microscopy
journal, August 2009


The HIV-2 Rev-response element: determining secondary structure and defining folding intermediates
journal, May 2013

  • Lusvarghi, Sabrina; Sztuba-Solinska, Joanna; Purzycka, Katarzyna J.
  • Nucleic Acids Research, Vol. 41, Issue 13
  • DOI: 10.1093/nar/gkt353

Contributions of Individual Domains to Function of the HIV-1 Rev Response Element
journal, August 2017

  • O'Carroll, Ina P.; Thappeta, Yashna; Fan, Lixin
  • Journal of Virology, Vol. 91, Issue 21
  • DOI: 10.1128/JVI.00746-17

Detection of HERV-K(HML-2) Viral RNA in Plasma of HIV Type 1-Infected Individuals
journal, October 2006

  • Contreras-Galindo, Rafael; Kaplan, Mark H.; Markovitz, David M.
  • AIDS Research and Human Retroviruses, Vol. 22, Issue 10
  • DOI: 10.1089/aid.2006.22.979

HIV-1 Infection Increases the Expression of Human Endogenous Retroviruses Type K (HERV-K) in Vitro
journal, January 2007

  • Contreras-Galindo, Rafael; López, Pablo; Vélez, Rosa
  • AIDS Research and Human Retroviruses, Vol. 23, Issue 1
  • DOI: 10.1089/aid.2006.0117

HERV-K–specific T cells eliminate diverse HIV-1/2 and SIV primary isolates
journal, November 2012

  • Jones, R. Brad; Garrison, Keith E.; Mujib, Shariq
  • Journal of Clinical Investigation, Vol. 122, Issue 12
  • DOI: 10.1172/JCI64560

HIV infection and HERV expression: a review
journal, January 2012


Expression of Human Endogenous Retrovirus Type K (HML-2) Is Activated by the Tat Protein of HIV-1
journal, May 2012

  • Gonzalez-Hernandez, M. J.; Swanson, M. D.; Contreras-Galindo, R.
  • Journal of Virology, Vol. 86, Issue 15
  • DOI: 10.1128/JVI.07215-11

Characterization of Human Endogenous Retroviral Elements in the Blood of HIV-1-Infected Individuals
journal, October 2011

  • Contreras-Galindo, R.; Kaplan, M. H.; Contreras-Galindo, A. C.
  • Journal of Virology, Vol. 86, Issue 1
  • DOI: 10.1128/JVI.00602-11

Molecular mechanisms by which HERV-K Gag interferes with HIV-1 Gag assembly and particle infectivity
journal, April 2017


HIV-1 Interacts with Human Endogenous Retrovirus K (HML-2) Envelopes Derived from Human Primary Lymphocytes
journal, March 2014

  • Brinzevich, D.; Young, G. R.; Sebra, R.
  • Journal of Virology, Vol. 88, Issue 11
  • DOI: 10.1128/JVI.00669-14

The HERV-K Human Endogenous Retrovirus Envelope Protein Antagonizes Tetherin Antiviral Activity
journal, September 2014

  • Lemaitre, C.; Harper, F.; Pierron, G.
  • Journal of Virology, Vol. 88, Issue 23
  • DOI: 10.1128/JVI.02234-14

Human endogenous retroviruses in neurologic disease
journal, January 2016


Structural basis for cooperative RNA binding and export complex assembly by HIV Rev
journal, October 2010

  • Daugherty, Matthew D.; Liu, Bella; Frankel, Alan D.
  • Nature Structural & Molecular Biology, Vol. 17, Issue 11
  • DOI: 10.1038/nsmb.1902

Implications of the HIV-1 Rev dimer structure at 3.2 A resolution for multimeric binding to the Rev response element
journal, March 2010

  • DiMattia, M. A.; Watts, N. R.; Stahl, S. J.
  • Proceedings of the National Academy of Sciences, Vol. 107, Issue 13
  • DOI: 10.1073/pnas.0914946107

The Structure of HIV-1 Rev Filaments Suggests a Bilateral Model for Rev-RRE Assembly
journal, July 2016


A new HIV-1 Rev structure optimizes interaction with target RNA (RRE) for nuclear export
journal, August 2018

  • Watts, Norman R.; Eren, Elif; Zhuang, Xiaolei
  • Journal of Structural Biology, Vol. 203, Issue 2
  • DOI: 10.1016/j.jsb.2018.03.011

alpha Helix-RNA Major Groove Recognition in an HIV-1 Rev Peptide-RRE RNA Complex
journal, September 1996


Mutational Definition of Functional Domains within the Rev Homolog Encoded by Human Endogenous Retrovirus K
journal, October 2000


Oligomerization and RNA binding domains of the type 1 human immunodeficiency virus Rev protein: a dual function for an arginine-rich binding motif.
journal, September 1991

  • Zapp, M. L.; Hope, T. J.; Parslow, T. G.
  • Proceedings of the National Academy of Sciences, Vol. 88, Issue 17
  • DOI: 10.1073/pnas.88.17.7734

Identification of a homogenous structural basis for oligomerization by retroviral Rev-like proteins
journal, August 2017


Reconstitution of an Infectious Human Endogenous Retrovirus
journal, January 2007


VARNA: Interactive drawing and editing of the RNA secondary structure
journal, April 2009