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J Biol Chem. 2017 Oct 20;292(42):17514-17524. doi: 10.1074/jbc.M117.799353. Epub 2017 Sep 6.

Thioredoxin-1 actively maintains the pseudokinase MLKL in a reduced state to suppress disulfide bond-dependent MLKL polymer formation and necroptosis.

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From the Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330006, China, and.
Proteomics Facility, National Institute of Biological Sciences, Beijing 102206, China.
From the Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390,


Necroptosis is an immunogenic cell death program that is associated with a host of human diseases, including inflammation, infections, and cancer. Receptor-interacting protein kinase 3 (RIPK3) and its substrate mixed lineage kinase domain-like protein (MLKL) are required for necroptosis activation. Specifically, RIPK3-dependent MLKL phosphorylation promotes the assembly of disulfide bond-dependent MLKL polymers that drive the execution of necroptosis. However, how MLKL disulfide bond formation is regulated is not clear. In this study we discovered that the MLKL-modifying compound necrosulfonamide cross-links cysteine 86 of human MLKL to cysteine 32 of the thiol oxidoreductase thioredoxin-1 (Trx1). Recombinant Trx1 preferentially binds to monomeric MLKL and blocks MLKL disulfide bond formation and polymerization in vitro Inhibition of MLKL polymer formation requires the reducing activity of Trx1. Importantly, shRNA-mediated knockdown of Trx1 promotes MLKL polymerization and sensitizes cells to necroptosis. Furthermore, pharmacological inhibition of Trx1 with compound PX-12 induces necroptosis in multiple cancer cell lines. Altogether, these findings demonstrate that Trx1 is a critical regulator of necroptosis that suppresses cell death by maintaining MLKL in a reduced inactive state. Our results further suggest new directions for targeted cancer therapy in which thioredoxin inhibitors like PX-12 could potentially be used to specifically target cancers expressing high levels of MLKL or MLKL short isoforms.


necrosis (necrotic death); serine/threonine protein kinase; thioredoxin; tumor necrosis factor (TNF); tumor therapy

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