The Tag7–Hsp70 cytotoxic complex induces tumor cell necroptosis via permeabilisation of lysosomes and mitochondria

Abstract Tag7 (PGRP-S, or PGLYRP1), an innate immunity protein, plays an important role in the immune defense system. It forms a stable cytotoxic complex with the heat shock protein Hsp70. This complex can induce an apoptotic or necroptotic tumor cell death by interacting with the TNFR1 receptor. In this study, we analyzed molecular events involved in the process of the Tag7–Hsp70-induced necroptosis. We found that Tag7 can bind to sTNFR1, a soluble fragment of the TNFR1 receptor, leading to an inhibition of the RIP1 dependent necroptosis. A major role in the downstream phases of the Tag7–Hsp70 induced necroptosis was played by an interaction between lysosomes and mitochondria. The interaction of Tag7–Hsp70 with the TNFR1 receptor triggered a certain sequence of events: at first, it activated RIP1 kinase, and later on, increased intracellular concentration of Са 2+ ions and an activation of calpains, which led to the permeabilization of the lysosomal membranes. The consequent release of the lysosomal enzymes, including cathepsins B and D, resulted in the depolarization of the mitochondrial membrane, ROS production, and eventual cell death.