Sci. STKE, 3 February 2004
TRANSCRIPTION Does HIV Nef Call Repressor Protein from the Nucleus to the Membrane?
The Nef protein encoded by HIV or SIV (human or simian immunodeficiency viruses, respectively) appears to function in pathogenesis through interactions in a signaling complex associated with the T cell receptor. Witte et al. identified an unexpected interaction partner of Nef that leads them to propose an unusual signaling mechanism for control of transcription. In a yeast two-hybrid screen, Nef interacted with the protein Eed (for embryonic ectodermal development factor). Eed is a member of the Polycomb group of proteins that regulates differentiation and proliferation of lymphocytes, apparently through interactions with promoters and with other proteins, to inhibit transcription. To confirm this potential interaction of Nef, which is usually localized at the plasma membrane, and Eed, normally found in the nucleus, the authors monitored localization of Eed in cells. Expression of Nef caused a transient localization of the Eed at the plasma membrane. Expression of a reporter construct based on the HIV long terminal repeat (LTR) was enhanced in Jurkat (a human leukemia T cell line) cells overexpressing Nef along with the protein kinase Lck, but a mutant form of Nef that did not interact with Eed was inactive. The authors propose therefore that recruitment of Eed away from the nucleus might relieve its effects on transcriptional activity. Support for such a role of Eed in normal cells came from experiments building on earlier observations that a protein related to Eed can associate with the cytoplasmic domain of integrins. Stimulation of integrins with Mn2+ and fibronectin in Jurkat cells caused endogenous Eed to move to the plasma membrane. Likewise, such integrin activation enhanced transcription of the HIV LTR reporter. Although noting that other explanations are not excluded, the authors propose that the HIV Nef protein may function in part by coopting a mechanism for control of transcriptional repression normally associated with acute integrin signaling.
V. Witte, B. Laffert, O. Rosorius, P. Lischka, K. Blume, G. Galler, A. Stilper, D. Willbold, P. D'Aloja, M. Sixt, J. Kolanus, M. Ott, W. Kolanus, G. Schuler, A. S. Baur, HIV-1 Nef mimics an integrin receptor signal that recruits the Polycomb group protein Eed to the plasma membrane. Mol. Cell 13, 179-190 (2004). [Online Journal]
Citation: Does HIV Nef Call Repressor Protein from the Nucleus to the Membrane? Sci. STKE 2004, tw39 (2004).
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