Abstract
The lentiviral protein Nef promotes infectivity and subverts immune surveillance of infected cells by downregulating cell surface proteins such as SERINC5 and MHC-I. The Nef proteins of HIV-1 group O, HIV-2, and SIV also target the restriction factor tetherin. These downregulatory activities are mediated by Nef hijacking the clathrin adaptor proteins AP-1 and AP-2 so as to redirect cargoes to the lysosome. Nef hijacks AP-1 in part by enhancing its Arf1-dependent trimerization. Nef and Arf1 in combination promote structurally and functionally distinct closed (trapped) and open (active) trimeric conformations. A new 3.5 Å cryo-EM structure of the AP-1:Arf-1:NL4-3 Nef:tetherin closed trimer reveals novel contacts that stabilize this hijacked complex. These data are interpreted in terms of a mechanism for trapping non-preferred cargoes such as tetherin with respect to HIV-1 M and N-group Nefs.
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