Moesin is required for HIV-1-induced CD4-CXCR4 interaction, F-actin redistribution, membrane fusion and viral infection in lymphocytes

Marta Barrero-Villar,AgustíN Valenzuela-FernáNdez,M ÁNgeles MuñOz-FernáNdez,Jonathan Barroso-GonzáLez,José RomáN Cabrero,Francisco SáNchez-Madrid,MóNica GordóN-Alonso,Susana ÁLvarez-Losada

doi:10.1242/jcs.035873

Abstract

The human immunodeficiency virus 1 (HIV-1) envelope regulates the initial attachment of viral particles to target cells through its association with CD4 and either CXCR4 or CCR5. Although F-actin is required for CD4 and CXCR4 redistribution, little is known about the molecular mechanisms underlying this fundamental process in HIV infection. Using CD4(+) CXCR4(+) permissive human leukemic CEM T cells and primary lymphocytes, we have investigated whether HIV-1 Env might promote viral entry and infection by activating ERM (ezrin-radixin-moesin) proteins to regulate F-actin reorganization and CD4/CXCR4 co-clustering. The interaction of the X4-tropic protein HIV-1 gp120 with CD4 augments ezrin and moesin phosphorylation in human permissive T cells, thereby regulating ezrin-moesin activation. Moreover, the association and clustering of CD4-CXCR4 induced by HIV-1 gp120 requires moesin-mediated anchoring of actin in the plasma membrane. Suppression of moesin expression with dominant-negative N-moesin or specific moesin silencing impedes reorganization of F-actin and HIV-1 entry and infection mediated by the HIV-1 envelope protein complex. Therefore, we propose that activated moesin promotes F-actin redistribution and CD4-CXCR4 clustering and is also required for efficient X4-tropic HIV-1 infection in permissive lymphocytes.

Highlights

The entry of HIV into a target cell requires the interaction of multiple receptor and co-receptor molecules with each viral envelope (Env) trimer to promote the formation of fusion pores (Doms, 2000; Kuhmann et al, 2000)
We propose that activated moesin promotes F-actin redistribution and CD4-CXCR4 clustering and is required for efficient X4-tropic human immunodeficiency virus 1 (HIV-1) infection in permissive lymphocytes
HIV-1 Env induces ERM phosphorylation and F-actin redistribution in CD4+ CXCR4+ lymphocytes It has recently been proposed that ERM proteins require phosphorylation to maintain their active state (Bretscher, 1999; Yonemura et al, 2002)

Summary

Introduction

The entry of HIV into a target cell requires the interaction of multiple receptor and co-receptor molecules with each viral envelope (Env) trimer to promote the formation of fusion pores (Doms, 2000; Kuhmann et al, 2000). HIV-1 viral entry occurs at specific cell-surface areas enriched in viral receptors, such as ruffles and microvilli (Singer et al, 2001; Steffens and Hope, 2003) The behavior of these structures is governed by cortical actin dynamics, which in turn depend on the activity of several actin cytoskeleton associated proteins such as those responsible for actin filament growth and capping (Mangeat et al, 1999). The FERM domain interacts with the cytoplasmic tails of several integral membrane proteins such as CD43, CD44, VCAM1, and ICAM1, ICAM2 and ICAM3, and mediates their cell-surface clustering (Barreiro et al, 2002; Heiska et al, 1998; Helander et al, 1996; Hirao et al, 1996; Matsui et al, 1998; Serrador et al, 1997; Takeuchi et al, 1994; Yonemura et al, 1993). The C-terminal domain of ERM molecules binds to actin filaments (Algrain et al, 1993)

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