Changing the Program

Science Signaling  26 Jan 2010:
Vol. 3, Issue 106, pp. ec28
DOI: 10.1126/scisignal.3106ec28

Kaposi’s sarcoma–associated herpesvirus (KSHV) infects endothelial cells and causes Kaposi’s sarcoma (KS), a blood vessel tumor in the skin characterized by spindle-shaped cells. KS occurs rarely in healthy individuals but is prevalent in people infected with HIV that are not receiving antiretroviral therapy. KSHV-infected cells are poorly differentiated, sharing markers of blood vessel endothelial cells (BECs) and lymphatic endothelial cells (LECs). Indeed, KSHV induces the production of BEC markers in infected LECs, but the mechanism responsible is unclear. Noting that KSHV encodes 17 microRNAs (miRNAs), Hansen et al. performed viral miRNA microarray screening of KS lesions from AIDS patients and found 10 KSHV miRNAs that were highly abundant. The mRNA for the transcription factor c-Maf was one of the mRNAs that was less abundant in LECs infected with a retrovirus encoding the KSHV miRNAs than it was in LECs infected with an empty vector. Analysis of the 3′ untranslated region (UTR) of c-Maf revealed the presence of 11 target sequences for KSHV miRNAs. c-Maf was the only member of the Maf family of transcription factors whose abundance in LECs was reduced by infection with KSHV. In addition, infection of LECs with KSHV increased the expression of a set of BEC-specific genes compared with that in uninfected LECs. Expression of these BEC-specific genes was inhibited by the expression of exogenous c-Maf without a 3′ UTR in the infected cells, suggesting a role for c-Maf as a transcriptional repressor. Thus, infected LECs were closer in characteristics to BECs than were uninfected LECs, resembling the poorly differentiated state of KSHV-infected cells observed in patients. Together, these data suggest that viral miRNAs, already known for their ability to modulate the host immune response, are also capable of affecting the differentiation state of infected cells.

A. Hansen, S. Henderson, D. Lagos, L. Nikitenko, E. Coulter, S. Roberts, F. Gratrix, K. Plaisance, R. Renne, M. Bower, P. Kellam, C. Boshoff, KSHV-encoded miRNAs target MAF to induce endothelial cell reprogramming. Genes Dev. 24, 195–205 (2010). [Abstract] [Full Text]