Figure 1. Working model of the endosomal recycling mechanism of LDLR. (A) LDLR and LDL-c are both endocytosed. LDLR can be directed to the lysosome for proteolysis, which is promoted by the proteins PCSK9 and IDOL, or it can be recycled and transported from the endosomes back to the cell surface. (B) Magnification of inset in A. At the endosomes LDLR is retrieved from the degradation pathway and directed to the recycling pathway. The CCC complex is formed by the COMMD proteins (COMMD1-10) and the core proteins (CCDC22, CCDC93 and C16orf62). The recycling is facilitated by the CCC and WASH complexes via a direct interaction between COMMD1 and LDLR. COMMD1-LDLR interaction is dependent on the NPxY domain in the cytosolic tail of LDLR. Loss of any CCC component (either a COMMD protein or a core component) destabilizes the complete CCC complex and results in diminished recycling of LDLR. The recruitment of the CCC and WASH complexes to the endosomes is partially dependent on retromer (VPS35, VPS29, VPS26), but it is still unclear whether LDLR recycling is retromer-dependent. Recently, retriever (DSCR3/VPS26c-C16orf62/VPS35L-VPS29) has been identified as a complex that retrieves transmembrane proteins from degradation pathways. Retriever is associated with the CCC complex but its exact function and its molecular organization in the CCC-WASH axis and in LDLR trafficking is still unclear. Like LDLR, also the recycling of the lipoprotein receptor LRP1 is dependent on the CCC complex, however, which other transmembrane proteins are recycled by the CCC complex remains to be determined.