8.a.149.  The Cytoskeleton-associated Protein 4 (CKAP4) Family

Cytoskeleton-associated protein 4 (CKAP4) is a palmitoylated type II transmembrane protein localized to the endoplasmic reticulum (ER). Knockout (KO) of CKAP4 in HeLaS3 cells induced the alterations of mitochondrial structures and increased the number of ER-mitochondria contact sites. To understand the involvement of CKAP4 in mitochondrial functions, the binding proteins of CKAP4 were explored, enabling identification of the mitochondrial porin voltage-dependent anion-selective channel protein2 (VDAC2), which is localized to the outer mitochondrial membrane (Harada et al. 2020). Palmitoylation at Cys(100) of CKAP4 was required for the binding of CKAP4 to VDAC2. In CKAP4 KO cells, the binding of the inositol trisphosphate receptor (IP3R) to VDAC2 was enhanced, the intramitochondrial Ca²⁺ concentration increased, and the mitochondrial membrane potential decreased. In addition, the CKAP4 KO mutation decreased the oxidative consumption rate, in vitro cancer cell proliferation under low-glucose conditions, and in vivo xenograft tumor formation. The phenotypes were not rescued by a palmitoylation-deficient CKAP4 mutant. Thus, CKAP4 plays a role in maintaining mitochondrial functions by binding to VDAC2 at ER-mitochondria contact sites in a process that requires palmitoylation (Harada et al. 2020).