Distinct trafficking pathways mediate Nef-induced and clathrin-dependent major histocompatibility complex class I down-regulation.
The human immunodeficiency virus type 1 Nef protein alters the post-Golgi stages of major histocompatibility complex class I (MHC-I) biogenesis. Presumed mechanisms involve the disclosure of a cryptic tyrosine-based sorting signal (YSQA) located in the cytoplasmic tail of HLA-A and -B heavy chains. We changed this signal for a prototypic sorting motif (YSQI or YSQL). Modified HLA-A2 molecules, termed A2-endo, displayed constitutively low surface levels and accumulated in a region close to or within the Golgi apparatus, a behavior reminiscent of wild-type HLA-A2 in Nef-expressing cells. However, several lines of evidence indicate that the action of prototypic signals on MHC-I trafficking differs from that of Nef. Internalization of surface A2-endo was more rapid and was associated with efficient recycling to the surface. A transdominant-negative mutant of dynamin-1 inhibited A2-endo constitutive internalization and Nef-induced CD4 down-regulation, whereas it did not affect the activity of Nef on MHC-I. Moreover, trafficking of A2-endo was still affected by the viral protein, indicating additive effects of prototypic signals and Nef. Therefore, distinct trafficking pathways regulate clathrin-dependent and Nef-induced MHC-I modulation.
Le Gall
S
S
Unité Rétrovirus et Transfert Génétique, URA CNRS 1930, France.
Buseyne
F
F
Trocha
A
A
Walker
B D
BD
Heard
J M
JM
Schwartz
O
O
D002966:Clathrin / Q000502:physiology*; D015536:Down-Regulation; D015693:Gene Products, nef / Q000502:physiology*; D006056:Golgi Apparatus / Q000502:physiology; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D006801:Humans; D015398:Signal Transduction; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus
D002966:Clathrin; D015693:Gene Products, nef; D015395:Histocompatibility Antigens Class I; D054311:nef Gene Products, Human Immunodeficiency Virus