Uncoating ATPase Hsc70 is recruited by invariant chain and controls the size of endocytic compartments

Targeting of class 11 major histocompatibility complex molecules to endocytic compartments is mediated by their association with the invariant chain (li). Although the identity of certain sorting signals located in li's cytoplasmic tail is known, proteins that interact with li's cytoplasmic tail in living cells remain to be identified. Synthesis of a biotinylated trimeric li's cytoplasmic tail allowed the retrieval of two proteins that interact with this domain. We identify one of them as the 70-kDa heat-shock cognate protein (hsc70), the uncoating ATPase of clathrin-coated vesicles, and the other as its mitochondrial homologue, the glucose-regulated protein grp7s. Expression of li in COS cells results in the formation of large endocytic compartments. We observe extensive colocalization of hsc70 with li in these macrosomes. Expression of a dominant-negative (K71M) green fluorescent protein-tagged version of hsc70 counteracted the ability of li to modify the endocytic pathway, demonstrating an interaction in vivo of li with hsc70 as part of the machinery responsible for macrosome formation.