Contents - College of Medical and Dental Sciences - University of ...
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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK<br />
Immunology I Abstract 10<br />
MOLECULAR MECHANISM OF BST2/TETHERIN DOWNREGULATION BY KSHV-K5<br />
M<strong>and</strong>ana Mansouri, Janet Douglas, Kasinath Viswanathan, Jean Gustin, Ashlee Moses <strong>and</strong><br />
Klaus Früh<br />
Vaccine <strong>and</strong> Gene Therapy Institute, Oregon Health <strong>and</strong> Science <strong>University</strong>, 505<br />
NW185th Ave, Beaverton, OR, 97001, USA<br />
Abstract<br />
K5 (MIR2) targets cellular immunostimulatory proteins for degradation by ubiquitinating<br />
their cytoplasmic tails. Using quantitative membrane proteomics we previously showed<br />
that bone marrow stromal antigen 2 (BST2) is downregulated by K5 (Bartee, 2006, PLoS<br />
Pathogens 2:e107). In similar experiments, we also observed that BST2 is<br />
downregulated by the HIV-1 immunomodulator Vpu. Recent reports showed that BST2 is<br />
an interferon-induced transmembrane glycoprotein that prevents egress <strong>of</strong> mature HIV-1<br />
virions by tethering them to the cell membrane, an antiviral activity that is overcome by<br />
Vpu (Neil, 2008, Nature 451). We determined the molecular mechanisms through which<br />
KSHV-K5 downregulates BST2/Tetherin in comparison to Vpu. In dermal microvascular<br />
endothelial cells, IFN-induced expression <strong>of</strong> BST2 is inhibited by K5. Upon infection with<br />
KSHV, BST2 expression is further increased in the presence <strong>of</strong> K5-specific siRNA<br />
suggesting that K5 downregulates virus-induced BST2 during de novo infection. We<br />
further show that Vpu downregulates BST2 from the cell surface by sequestering it in the<br />
Golgi whereas K5 targets BST2 for degradation since steady state levels <strong>of</strong> total BST2 or<br />
cell surface BST2 are dramatically reduced in K5-expressing cells. Taken together with<br />
other data to be presented, we conclude that BST2 is a bona-fide target <strong>of</strong> K5. The role<br />
<strong>of</strong> BST2/Tetherin in modulating KSHV-infection is unknown. We will present data to<br />
address whether, in the absence <strong>of</strong> K5, BST2 interferes with egress <strong>of</strong> KSHV virions. Our<br />
data suggest that BST2 is part <strong>of</strong> the innate antiviral response to viral infection <strong>and</strong> that<br />
viruses <strong>of</strong> different genera have developed distinct countermeasures against this protein.<br />
Presenting author Email: dougljan@ohsu.edu<br />
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