Activation of Lysosomal Retrograde Transport Triggers TPC1-IP3R1 Ca²⁺ Crosstalk at Lysosome-ER MCSs Leading to Lethal Depleting of ER Calcium.

ABSTRACT: Inter-organellar signaling linkages in oncology are increasingly elucidated. However, the impact of lysosome-endoplasmic reticulum (ER) interaction on tumor cell fate remains relatively unexplored. A novel interaction between lysosomes and the ER, mediated by the flavonoid LW-213 through targeting LIMP2 (lysosomal integral membrane protein type 2)to activate a lysosomal repair pathway, is identified in acute myeloid leukemia (AML). This leads to activated RAB7A activity, enhancing lysosomal retrograde transport to the perinuclear region and increasing contact at lysosome-ER membrane contact sites (MCSs). Close proximity of TPC1 to IP3R1 at these sites generates a concentrated calcium microdomain, triggering Ca²⁺-induced Ca²⁺ release, which causes cytoplasmic calcium t

SUBMITTER: Zhu MY 

PROVIDER: S-EPMC12533322 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature