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. Author manuscript; available in PMC: 2015 Jan 22.
Published in final edited form as: Biochem J. 2009 Jun 12;421(1):1–15. doi: 10.1042/BJ20081016

Figure 6. ‘Signalling’ model of Nef-mediated down-regulation of cell-surface MHC-I.

Figure 6

Step 1: Nef binds PACS-2 through its acidic cluster (EEEE65) and is targeted to the late Golgi/TGN. Step 2: at the TGN, Nef PXXP75 binds and activates a TGN-localized SFK. Step 3: the activated Nef–SFK complex recruits and activates ZAP-70/Syk. Tyrosine-phosphorylated ZAP-70/Syk then binds a class I PI3K. Step 4: Nef-stimulated class I PI3K generates PIP3 on the inner leaflet of the plasma membrane. Step 5: an ARF6 guanine-nucleotide-exchange factor (ARF6-GEF) is recruited to PIP3 at the plasma membrane. Step 6: the recruited ARF6-GEF in turn activates ARF6. Step 7: MHC-I is rapidly endocytosed from the plasma membrane to internal endosomal compartments. Steps 8 and 9: sequestration of newly internalized MHC-I molecules to a paranuclear region requires the Nef Met20 and its interaction with AP-1. The precise step of Nef-mediated MHC-I down-regulation requiring PACS-1 is unclear but the ability of PACS-1 to bind Nef and AP-1 raises the possibility that PACS-1 may contribute to the Met20-dependent internalization of MHC-I molecules.