How might VPS13C influence insulin secretion in vivo? Clues might be gleaned by comparisons with other members of the VPS13 family. BLAST analysis of the protein sequences of the four family members indicates that VPS13C is most similar to VPS13A, sharing 41% identity (73) and the two proteins possess several common domains and have similar NH2 and COOH termini, indicating that they may have similar functions (73). Both can attach to membranes, although VPS13C has intramolecular duplications vs. VPS13A, which may imply neofunctionalization (i.e., the acquiring of new roles) compared with VPS13A (73). As noted above, a loss of VPS13A (also called chorein) expression leads to the rare neurodegenerative disease chorea-acanthocytosis (ChAc) (53, 71). Symptoms include cognitive dysfunction, hyperkinetic movement disorder, and erythrocyte acanthocytosis (72), leading to significant disability and a reduced life expectancy. Since the discovery of the cause of ChAc, much work has been done to investigate the molecular function of VPS13A. The protein has been localized to endosomal structures in yeast and erythrocytes (14, 28, 64, 70) as well as to the Golgi, and cofractionates with dense-core vesicles in synaptosomes (25, 34). VPS13A is also implicated in a plethora of cellular processes in different settings, including regulation of the actin cytoskeleton (2, 18, 64), protein trafficking (7), membrane morphogenesis (48), autophagy (45), and phagocytosis (59). Cells depleted of VPS13A have decreased levels of PI(4)P and of phosphorylated PI3K (18, 47, 48). Importantly, further evidence for a role for VPS13A in the control of regulated exocytosis was provided recently by Hayashi et al. (25), who demonstrated that VPS13A is localized to neurites in dopaminergic PC12 cells. These findings are thus strongly reminiscent of our findings here of colocalization between VPS13C and insulin in human β-cells (Fig. 12). The role for VPS13A in phosphoinositide (PI) metabolism is a function that is conserved between yeast and human orthologs and a possible mechanism by which VPS13A can function in so many different cellular processes (18, 47–49). If VPS13C were to have similar functions in β-cells as VPS13A, we would hypothesize that the former might be involved in protein trafficking, potentially through the regulation of PI metabolism.