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