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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
Necroptosis: A Pathogenic Negotiator in Human Diseases
Hitesh Singh Chaouhan1, Ch Vinod2, Nikita Mahapatra2
1Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan.
Abstract:
Over the past few decades, mechanisms of programmed cell death have attracted the scientific community because they are involved in diverse human diseases. Initially, apoptosis was considered as a crucial mechanistic pathway for programmed cell death; recently, an alternative regulated mode of cell death was identified, mimicking the features of both apoptosis and necrosis. Several lines of evidence have revealed that dysregulation of necroptosis leads to pathological diseases such as cancer, cardiovascular, lung, renal, hepatic, neurodegenerative, and inflammatory diseases. Regulated forms of necrosis are executed by death receptor ligands through the activation of receptor-interacting protein kinase (RIPK)-1/3 and mixed-lineage kinase domain-like (MLKL), resulting in the formation of a necrosome complex. Many papers based on genetic and pharmacological studies have shown that RIPKs and MLKL are the key regulatory effectors during the progression of multiple pathological diseases. This review focused on illuminating the mechanisms underlying necroptosis, the functions of necroptosis-associated proteins, and their influences on disease progression. We also discuss numerous natural and chemical compounds and novel targeted therapies that elicit beneficial roles of necroptotic cell death in malignant cells to bypass apoptosis and drug resistance and to provide suggestions for further research in this field.
Insights
Necroptosis, a regulated cell death pathway involving RIPK-1/3 and MLKL, is implicated in various diseases. Targeting necroptosis offers potential therapeutic strategies for conditions like cancer and inflammatory diseases.
Area of Science:
- Molecular Biology
- Cell Biology
- Pathology
Background:
- Programmed cell death mechanisms are crucial in human health and disease.
- Necroptosis, a regulated form of necrosis, shares features with apoptosis but has distinct molecular players.
- Dysregulation of necroptosis is linked to numerous pathological conditions, including cancer, cardiovascular, inflammatory, and neurodegenerative diseases.
Purpose of the Study:
- To elucidate the molecular mechanisms of necroptosis.
- To explore the role of necroptosis-associated proteins (RIPK-1/3, MLKL) in disease pathogenesis.
- To review therapeutic strategies targeting necroptosis for disease treatment.
Main Methods:
- Review of existing genetic and pharmacological studies on necroptosis.
- Analysis of the function of key necroptosis-associated proteins.
- Discussion of natural compounds and targeted therapies affecting necroptosis.
Main Results:
- Necroptosis is executed via receptor-interacting protein kinase (RIPK)-1/3 and mixed-lineage kinase domain-like (MLKL) activation, forming a necrosome complex.
- RIPKs and MLKL are critical regulators in the progression of multiple pathological diseases.
- Targeting necroptosis can induce cancer cell death, potentially overcoming apoptosis resistance.
Conclusions:
- Understanding necroptosis mechanisms and associated proteins is vital for disease intervention.
- Therapeutic strategies modulating necroptosis show promise for treating various pathologies, particularly cancer.
- Further research into necroptosis modulators may yield novel treatments for drug-resistant diseases.
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