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

Journal Article · · Journal of Molecular Biology
 [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)
+ Show Author Affiliations

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.

Research Organization:
United States Naval Academy, Annapolis, MD (United States)
Sponsoring Organization:
USDOE Office of Science (SC); National Institutes of Health (NIH)
Grant/Contract Number:
AC02-06CH11357; HHSN26120080001E
OSTI ID:
1713061
Alternate ID(s):
OSTI ID: 1775965
Journal Information:
Journal of Molecular Biology, Vol. 432, 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.; ISSN 0022-2836
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
HERV-K
RcRE
small-angle X-ray scattering
atomic force microscopy
HIV-1 Rev