Upon cytokine stimulation, they induce signalling cascades promoting cell proliferation in the immune response (Gaffen, 2001). These receptors include the β-chain of the interleukin-2 and interleukin-15 receptors (IL-2Rβ) and the common cytokine γ-chain (IL-2Rγc) of the receptors for interleukins 2, 4, 7, 9, 15 and 21. Several clathrin-independent routes have been uncovered however, their molecular mechanisms are not fully understood (Howes et al, 2010b Sandvig et al, 2011).Ĭytokine receptors, like IL-2R, were among the first physiological examples of cargos taken up by a clathrin-independent mechanism (Subtil et al, 1994 Lamaze et al, 2001 Sauvonnet et al, 2005). In this process, the cargos are recruited into clathrin-coated pits initiated from a flat membrane that then form clathrin-coated vesicles (Harding et al, 1983 McMahon & Boucrot, 2011). So far, the best studied pathway is clathrin-dependent endocytosis, involving many well-characterized factors (Mousavi et al, 2004). Over the years, different endocytic pathways have been identified. Besides the entry of nutrients, endocytosis is involved in many processes, such as cell migration, division, signalling, differentiation and immune response (Sigismund et al, 2012). Altogether, our work identifies the spatio-temporal specific role of factors initiating clathrin-independent endocytosis by a unique mechanism that does not depend on the deformation of a flat membrane, but rather on that of membrane protrusions.Įndocytosis is a crucial mechanism that eukaryotic cells use to internalize, both actively and specifically, multiple components. Finally, our data reveal that dynamin acts as a transition controller for the recruitment of Arp2/3 activators required for IL-2R endocytosis. In addition, using total internal reflection fluorescent microscopy (TIRF) and automated analysis we demonstrate that two timely distinct bursts of actin polymerization are required during IL-2R uptake, promoted first by the WAVE complex and then by N-WASP. The WAVE complex interacts with IL-2R, via a WAVE-interacting receptor sequence (WIRS) present in the receptor polypeptide, and allows for receptor clustering close to membrane protrusions. We identify the WAVE complex as a specific endocytic actor. Our electron microscopy (EM) and tomography studies reveal that IL-2R-pits and vesicles are initiated at the base of protrusions. However, this process lacks morphological and dynamic data. A clathrin- and caveolin-independent endocytosis pathway is used by important physiological cargos, including interleukin-2 receptors (IL-2R). Endocytosis controls many functions including nutrient uptake, cell division, migration and signal transduction.
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