Progress in study on the final executor of necroptosis MLKL and its inhibitors

Abstract

Necroptosis is one of the regulated cell death, which involves receptor interacting protein kinase (RIPK) 1/RIPK3/mixed lineage kinase domain like protein (MLKL) signaling pathway. Among them, MLKL is the final execution of necroptosis. The formation of RIPK1/RIPK3/MLKL necrosome induces the phosphorylated MLKL, and the activated MLKL penetrates into the membrane bilayer to form membrane pores, which damages the integrity of the membrane and leads to cell death. In addition to participating in necroptosis, MLKL is also closely related to other cell death, such as NETosis, pyroptosis, and autophagy. Therefore, MLKL is involved in the pathological processes of various diseases related to abnormal cell death pathways (such as cardiovascular diseases, neurodegenerative diseases and cancer), and may be a therapeutic target of multiple diseases. Understanding the role of MLKL in different cell death can lay a foundation for seeking various MLKL-related disease targets, and also guide the development and application of MLKL inhibitors.

Keywords: cancer; cardiovascular diseases; mixed lineage kinase domain like protein; necroptosis; neurodegenerative diseases.

图1

坏死样凋亡信号通路示意图 Figure 1 Schematic diagram for the signaling pathway of necroptosis TNF-α: Tumor necrosis factor-α; TNFR1: Tumor necrosis factor receptor 1; TRADD: TNF receptor-associated death domain; TRAF2: TNF receptor associated factor 2; cIAP1/2: Cellular inhibitors of apoptosis proteins 1 and 2; LUBAC: Linea ubiquitin chain assembly complex; CYLD: Cylindromatosis; FADD: Fas-associating protein with a novel death domain; CASP8: Caspase-8; MAPK: Mitogen-activated protein kinase; NF-κB: Nuclear factor kappa-B; psKD: Pesudokinase domin; RIPK: Receptor interacting protein kinase; MLKL: Mixed lineage kinase domain like protein.