Polychlorinated biphenyl quinone regulates MLKL phosphorylation that stimulates exosome biogenesis and secretion via a short negative feedback loop

Polychlorinated biphenyls (PCBs) are one of the most refractory organic environmental pollutants that ubiquitous existence in nature. Due to the polymorphism of their metabolic pathway and corresponding downstream metabolites, PCBs' toxicities are complicated and need extended investigation. In the present study, we discovered a novel regulatory mechanism of PCB quinone metabolite-driven programmed cell death (PCD), namely, necroptosis. We first confirmed that PCB quinone induces cancerous HeLa and MDA-MB-231 cells necroptosis via the phosphorylation of mixed lineage kinase domain-like MLKL (p-MLKL). Then, we found that PCB quinone-stimulated p-MLKL enhances exosome biogenesis and secretion. Exosome interacts with p-MLKL and releases p-MLKL to the outside of the cell, and ultimately alleviating PCB quinone-induced necroptosis. The inhibition of exosome secretion by GW4869 significantly elevated necroptotic level, indicating the establishment of a short negative feedback loop of MLKL-exosome secretion upon PCB quinone challenge. Since exosome-mediated signaling showed great implications in various human diseases, this work may provide a new mechanism for PCBs-associated toxicity. (C) 2020 Elsevier Ltd. All rights reserved.

Automated summary

In this study, a novel regulatory mechanism of PCB quinone-induced necroptosis was discovered, involving the enhancement of exosome biogenesis and secretion. Inhibition of exosome secretion led to elevated necroptotic levels, indicating the presence of a negative feedback loop between MLKL and exosome secretion. This work provides a potential new mechanism for PCBs-associated toxicity and highlights the significance of exosome-mediated signaling in human diseases.