FasL on the surface of Tag7 (PGRP-S)-activated lymphocytes induces necroptosis in HLA-negative tumor cells with the involvement of lysosomes and mitochondria.

Recently we have found that cytokine IL-2 and innate immunity protein Tag7 activate cytotoxic lymphocytes that kill HLA-negative tumor cells, inducing both apoptosis and necroptosis. Here we decrypt the processes, taking part in necroptosis execution after FasL-Fas interaction. Necroptosis begins with RIPK1 activation and necrosome formation. Subsequent activation of MLKL results in the increase of Ca2+ level in the cell and activation of Ca2+-dependent enzymes causing lysosomal membrane permeabilization and the release of cathepsins to the cytosol. STAT3 translocation to the mitochondria and binding to a component of the respiratory chain complex I causes ROS accumulation. We have shown that transduction of necroptotic signal via TNFR1 and Fas has many common points. It is known that apoptosis plays a major role in physiological cell death; however, under pathological conditions necroptosis is very common. That is why the detailed mechanisms of FasL-Fas necroptosis can help in understanding the processes of elimination of tumor cells that have blocked apoptosis signal transduction.