Previous studies have established the antitumor activity of curcumin, a major component of turmeric. Increasing evidence indicates that curcumin induces autophagy, the activation of mitogen-activated protein kinase (MAPK) intracellular signaling pathways, and reactive oxygen species (ROS)-mediated cell death. The c-Jun NH2-terminal kinase (JNK)-associated leucine zipper protein (JLP), a scaffold protein for MAPK signaling pathways, has been identified as a candidate biomarker for cancer. In this study, we explored the role of JLP in curcumin-induced cancer cell death. We found that JLP knockdown (KD) increases cell death and intracellular ROS levels. Furthermore, JLP KD impaired lysosomal accumulation around perinuclear regions, which led to the inhibition of autophagosome-lysosome fusion, and attenuated p38 MAPK activation in curcumin-treated cells. The decreases in cell viability and p38 MAPK activation were reversed by expressing wild-type JLP but not a JLP mutant lacking the p38 MAPK-binding domain. In addition, the inactivation of a key gene involved in autophagy increased sensitivity to curcumin-induced cell death. Together, these results suggest that JLP mediates the induction of autophagy by regulating lysosome positioning and p38 MAPK signaling, indicating an overall protective role in curcumin-induced ROS-mediated cancer cell death. (C) 2019 Elsevier Inc. All rights reserved.