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© The Rockefeller University Press, 0021-9525/1997//37 $5.00
The Journal of Cell Biology, Volume 139, Number 1, , 1997 37-47

Article

Nef-mediated Clathrin-coated Pit Formation



Michelangelo Foti*, Aram Mangasarian{ddagger}, Vincent Piguet*,{ddagger}, Daniel P. Lew§, Karl-Heinz Krause§, Didier Trono{ddagger}, and Jean-Louis Carpentier*

* Department of Morphology, Centre Médical Universitaire, § Division of Infectious Diseases, Hôpital Cantonal Universitaire, University of Geneva 4, Switzerland 1211; and {ddagger} Infectious Disease Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037

The sequence of events leading to clathrin-coated pit (CCP) nucleation on the cell surface and to the incorporation of receptors into these endocytic structures is still imperfectly understood. In particular, the question remains as to whether receptor tails initiate the assembly of the coat proteins or whether receptors migrate into preformed CCP. This question was approached through a dissection of the mechanisms implemented by Nef, an early protein of human and simian immunodeficiency virus (HIV and SIV, respectively), to accelerate the endocytosis of cluster of differentiation antigen type 4 (CD4), the major receptor for these viruses. Results collected showed that: (a) Nef promotes CD4 internalization via an increased association of CD4 with CCP; (b) the Nef-mediated increase of CD4 association with CCP is related to a doubling of the plasma membrane area occupied by clathrin-coated structures; (c) this increased CCP number at the plasma membrane has functional consequences preferentially on CD4 uptake and does not significantly affect transferrin receptor internalization or fluid-phase endocytosis; (d) the presence of a CD4 cytoplasmic tail including a critical dileucine motif is required to induce CCP formation via Nef; and (e) when directly anchored to the cytoplasmic side of the plasma membrane, Nef itself can promote CCP formation. Taken together, these observations lead us to propose that CD4 can promote CCP generation via the connector molecule Nef. In this model, Nef interacts on one side with CD4 through a dileucine-based motif present on CD4 cytoplasmic tail and on the other side with components of clathrin-coated surface domain (i.e., adaptins). These Nef-generated complexes would then initiate the nucleation of CCP.

Abbreviations used in this paper: AP, adaptor protein; CCP, clathrin-coated pit(s); CD4, cluster of differentiation antigen type 4; Tf-R, transferrin receptor.

Address all correspondence to Jean-Louis Carpentier, Department of Morphology, Centre Médical Universitaire, 1, rue Michel-Servet, 1211 Geneva 4, Switzerland. Tel.: 41.22.7025201. Fax: 41.22.7025260. E-mail: Jean-LouisCarpentier{at}medecine.unige.ch

2. These values do not integrate the curvature of CCP which, if taken into account, would have amplified the difference in favor of CCP.


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