Cell Death and Inflammation Lab, VIB Center for Inflammation Research, Ghent, Belgium.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Cell Death Differ. 2021 Jun;28(6):1757-1772. doi: 10.1038/s41418-021-00785-0. Epub 2021 May 5.
Mixed lineage kinase domain-like protein (MLKL) emerged as executioner of necroptosis, a RIPK3-dependent form of regulated necrosis. Cell death evasion is one of the hallmarks of cancer. Besides apoptosis, some cancers suppress necroptosis-associated mechanisms by for example epigenetic silencing of RIPK3 expression. Conversely, necroptosis-elicited inflammation by cancer cells can fuel tumor growth. Recently, necroptosis-independent functions of MLKL were unraveled in receptor internalization, ligand-receptor degradation, endosomal trafficking, extracellular vesicle formation, autophagy, nuclear functions, axon repair, neutrophil extracellular trap (NET) formation, and inflammasome regulation. Little is known about the precise role of MLKL in cancer and whether some of these functions are involved in cancer development and metastasis. Here, we discuss current knowledge and controversies on MLKL, its structure, necroptosis-independent functions, expression, mutations, and its potential role as a pro- or anti-cancerous factor. Analysis of MLKL expression patterns reveals that MLKL is upregulated by type I/II interferon, conditions of inflammation, and tissue injury. Overall, MLKL may affect cancer development and metastasis through necroptosis-dependent and -independent functions.
混合谱系激酶结构域样蛋白（MLKL）作为细胞程序性坏死的执行者而出现，这是一种 RIPK3 依赖性的调节性细胞坏死形式。逃避细胞死亡是癌症的特征之一。除了细胞凋亡，一些癌症通过例如 RIPK3 表达的表观遗传沉默来抑制与细胞坏死相关的机制。相反，癌细胞引发的细胞坏死相关炎症可以促进肿瘤生长。最近，在受体内化、配体-受体降解、内体运输、细胞外囊泡形成、自噬、核功能、轴突修复、中性粒细胞胞外诱捕网（NET）形成和炎症小体调节中揭示了 MLKL 的非细胞坏死依赖性功能。关于 MLKL 在癌症中的精确作用以及这些功能是否参与癌症的发生和转移，人们知之甚少。在这里，我们讨论了关于 MLKL 的当前知识和争议，包括其结构、非细胞坏死依赖性功能、表达、突变以及作为促癌或抑癌因子的潜在作用。对 MLKL 表达模式的分析表明，I/II 型干扰素、炎症和组织损伤条件上调 MLKL。总的来说，MLKL 可能通过细胞坏死依赖性和非依赖性功能影响癌症的发生和转移。
