Abstract: The present invention provides for up- and down-regulation of cellular autophagy, e.g., for treating cancer or neurological disease. The invention results, in part, from discovery of two novel proteins, ATG14L (previously called “BISC”) and Rubicon (previously called “BIRC”), which bind to a Class III phophatidylinositol 3?-kinase (PI3K)/Vps34-Beclin 1 autophagic complex. ATG14L and Rubicon each regulate autophagic activity in an opposing manner. ATG14L and Rubicon can be used, for example, to increase/decrease autophagic activity, to increase/decrease PI3K/Vps34 kinase activity, and in so doing, treat diseases and disorders, such as cancer, neurodegenerative disease, stroke, metabolic disease, and age-related disease. ATG14L can increase autophagic activity and PI3K/Vps34 kinase activity; and Rubicon can decrease autophagic activity and PI3K/Vps34 kinase activity.