Functional Specialization of Clathrin‐Independent Endocytic Routes: Mechanisms and Cellular Roles

Clathrin-independent endocytosis (CIE) comprises a diverse repertoire of internalization mechanisms that operate in parallel with clathrin-mediated endocytosis. While these mechanisms share certain characteristics, they are governed by distinct molecular principles and regulatory logic. In this review, we provide an overview of CIE mechanisms, with a particular focus on the functional specialization of individual routes. We trace the historical emergence of CIE concepts and highlight how bacterial toxins and viruses have served as pivotal discovery tools, revealing lipid-driven and lectin-mediated mechanisms of membrane bending and internalization. Furthermore, we delineate the molecular frameworks of major CIE mechanisms and discuss experimental strategies for their dissection. We emphasize how the selection of a specific endocytic route dictates cargo fate, directing receptors and adhesion molecules toward recycling, retrograde trafficking, or degradation to modulate signaling amplitude, polarity, migration and epithelial barrier functions. Finally, we offer an evolutionary perspective on "coatless" CIE-like mechanisms.