Homeoprotein intercellular transfer, the hidden face of cell-penetrating peptides

Cell-Penetrating Peptides (CPPs) are small peptides internalized by live cells, gaining access to their cytoplasm and intracellular organelles (i.e., mitochondria, nucleus) and are used as pharmacological tools. This is indeed a very important issue, fully justifying the efforts of several groups to better understand the mechanisms of peptide transduction and to verify if and how this strategy can be translated into therapeutic improvements. However, the discovery of peptide transduction is a consequence of that of a novel signaling mechanism based on the intercellular transfer of homeoprotein transcription factors. Indeed, the first and probably most popular CPPs (Tat and Penetratin) correspond to domains that drive TAT (HIV) and homeoprotein transcription factors into the cells. These findings have fostered several studies on transduction and allowed the design of "nonnatural" CPPs. As useful as they are, these lines of research have, in general, neglected the fact that protein transduction is a signaling mechanism, in its own right, with important physiological functions. In this chapter, I describe some of these functions and propose that this class of signaling molecules, in particular homeoproteins, may also be used as therapeutic agents.