Résumés
Résumé
En 1988, A.D. Frankel et C.O. Pabo proposent que le facteur de transcription TAT du virus de l’immunodéficience humaine (VIH) est internalisé par les cellules. Parallèlement, des travaux développés dans notre laboratoire démontrent que le domaine de fixation sur l’ADN (l’homéodomaine) d’un facteur de transcription de la famille des homéoprotéines passe directement de l’extérieur vers l’intérieur de la cellule. La séquence responsable de cette internalisation est la troisième hélice de l’homéodomaine, longue de 16 acides aminés. La conservation de cette structure dans tous les facteurs de transcription de la famille des homéoprotéines suggère que l’internalisation est une propriété partagée par la grande majorité de ces protéines. Ces études ont ouvert la voie au concept physiologique de protéine messagère et au développement de peptides de transduction. Ces peptides sont utilisés comme vecteurs pour internaliser dans les cellules, in vitro et in vivo, des cargos hydrophiles de composition et de structure très variées. Cet article fait le point sur les mécanismes impliqués, les utilisations vérifiées ou potentielles de ces peptides et les difficultés rencontrées dans certaines de leurs utilisations, sans oublier les implications physiologiques de ce phénomène.
Summary
Tranduction peptides that cross the plasma membrane of live cells are commonly used for the in vitro and in vivo targeting of hydrophilic drugs into the cell interior. Although this family of peptides has recently increased and will probably continue to do so, the two mainly used peptides are derived from transcription factors. Indeed, TAT is a 12 amino acid long arginine-rich peptide present in the HIV transcription factor, and penetratin - or its variants - corresponds to 16 amino acids that define the highly conserved third helix of the DNA-binding domain (homeodomain) of homeoprotein transcription factors. In this review, we shall recall the different steps that have led to the discovery of transduction peptides and present the most likely hypotheses concerning the mechanisms involved in their internalization. At the risk of being incomplete or, even, biased, we shall concentrate on penetratins and TAT. The reason is that these peptides have been studied for over ten years leading to the edification of robust knowledge regarding their properties. This attitude will not preclude comparisons with other peptides, if necessary. Our goal is to describe the mode of action of these transduction peptides, their range of activity in term of cell types that accept them and cargoes that they can transport, and, also, some of the limitations that one can encounter in their use. Finally, based on the idea that peptide transduction is the technological face of a physiological property of some transcription factors, we shall discuss the putative physiological function of homeoprotein transduction, and, as a consequence, the possibility to use these factors as therapeutic proteins.
Parties annexes
Références
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