KSHV LANA inhibits TGF-β signaling through epigenetic silencing of the TGF-β type II receptor

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Abstract

Signaling through the transforming growth faetor-β (TGF-β) pathway results in growth inhibition and induction of apoptosis in various cell types. We show that this pathway is blocked in Kaposi sarcoma herpesvirus (KSHV)-infected primary effusion lymphoma through downregulation of the TGF-β type II receptor (TβRII) by epigenetic mechanisms. Our data also suggest that KSHV infection may result in lower expression of TβRII in Kaposi sarcoma and multicentric Castleman disease. KSHV-encoded LANA associates with the promoter of TβRII and leads to its methylation and to the deacetylation of proximal histones. Reestablishment of signaling through this pathway reduces viability of these cells, inferring that KSHV-mediated blockage of TGF-β signaling plays a role in the establishment and progression of KSHV-associated neoplasia. These data suggest a mechanism whereby KSHV evades both the antiproliferative effects of TGF-p signaling by silencing TβRll gene expression and immune recognition by suppressing TGF-β-responsive immune cells through the elevated secretion of TGF-β1. © 2008 by The American Society of Hematology.

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Di Bartolo, D. L., Cannon, M., Liu, Y. F., Renne, R., Chadburn, A., Boshoff, C., & Cesarman, E. (2008). KSHV LANA inhibits TGF-β signaling through epigenetic silencing of the TGF-β type II receptor. Blood, 111(9), 4731–4740. https://doi.org/10.1182/blood-2007-09-110544

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