HIV-1 Nef Disrupts Antigen Presentation Early in the Secretory Pathway

Maya Williams,Matthew R Kasper,Rebekah I Fleis,Jeremiah F Roeth,Kathleen L Collins,Tracey M Filzen

doi:10.1074/jbc.m413538200

Maya Williams, Matthew R Kasper + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m413538200

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Abstract

Human immunodeficiency virus, type 1 Nef disrupts viral antigen presentation and promotes viral immune evasion from cytotoxic T lymphocytes. There is evidence that Nef acts early in the secretory pathway to redirect major histocompatibility complex class I (MHC-I) from the trans-Golgi network to the endolysosomal pathway. However, a competing model suggests that Nef acts much later by accelerating MHC-I turnover at the cell surface. Here we demonstrate that Nef targets early forms of MHC-I molecules in the endoplasmic reticulum by preferentially binding hypophosphorylated cytoplasmic tails. The Nef-MHC-I complex migrates normally into the Golgi apparatus but subsequently fails to arrive at the cell surface and become phosphorylated. Cell type-specific differences in the rate of MHC-I transport through the secretory pathway correlate with responsiveness to Nef and co-precipitation of adaptor protein 1 with the Nef.MHC-I complex. We propose that the assembly of a Nef.MHC-I.adaptor protein 1 complex early in the secretory pathway is important for Nef activity.

Highlights

Cytotoxic T lymphocytes (CTL(s))1 are important for preventing and controlling viral infections [1,2,3,4,5,6,7,8,9]
Based on data collected in non-T cell lines, it was thought that Nef reduced major histocompatibility complex class I (MHC-I) cell surface expression by accelerating endocytosis and promoting retrograde transport of internalized MHC-I to the trans-Golgi network (TGN) [18, 23, 24]
The Effect of Nef on MHC-I Phosphorylation—MHC-I is phosphorylated on its cytoplasmic tail late in its biosynthesis after it has reached the TGN (39 – 41)

Summary

Introduction

Cytotoxic T lymphocytes (CTL(s)) are important for preventing and controlling viral infections [1,2,3,4,5,6,7,8,9]. Based on data collected in non-T cell lines, it was thought that Nef reduced MHC-I cell surface expression by accelerating endocytosis and promoting retrograde transport of internalized MHC-I to the trans-Golgi network (TGN) [18, 23, 24]. AP-1 is a heterotetrameric protein complex that sorts proteins by binding recognition sequences in cytoplasmic tails and linking them to clathrin In this manner, proteins are directed from the TGN into the endolysosomal pathway. Nef targets MHC-I from the TGN to the lysosomes for degradation by promoting a physical interaction between AP-1 and the cytoplasmic tail of MHC-I [26] It is not known why this pathway is more active in T cells than other cell types

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