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MAPK/MAK/MRK overlapping kinase (MOK) controls microglial inflammatory/type-I IFN responses via Brd4 and is involved
Jesús A Pérez-Cabello1,2, Lucía Silvera-Carrasco1,2, Jaime M Franco1
1Centro Andaluz de Biología Molecular y Medicina Regenerativa, Universidad de Sevilla-Consejo Superior de Investigaciones Científicas, Seville 41092, Spain.
Abstract:
Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease affecting motor neurons and characterized by microglia-mediated neurotoxic inflammation whose underlying mechanisms remain incompletely understood. In this work, we reveal that MAPK/MAK/MRK overlapping kinase (MOK), with an unknown physiological substrate, displays an immune function by controlling inflammatory and type-I interferon (IFN) responses in microglia which are detrimental to primary motor neurons. Moreover, we uncover the epigenetic reader bromodomain-containing protein 4 (Brd4) as an effector protein regulated by MOK, by promoting Ser492-phospho-Brd4 levels. We further demonstrate that MOK regulates Brd4 functions by supporting its binding to cytokine gene promoters, therefore enabling innate immune responses. Remarkably, we show that MOK levels are increased in the ALS spinal cord, particularly in microglial cells, and that administration of a chemical MOK inhibitor to ALS model mice can modulate Ser492-phospho-Brd4 levels, suppress microglial activation, and modify the disease course, indicating a pathophysiological role of MOK kinase in ALS and neuroinflammation.
Insights
Amyotrophic lateral sclerosis (ALS) involves harmful inflammation from microglia. This study identifies MAPK/MAK/MRK overlapping kinase (MOK) as a key regulator of this neuroinflammation, offering a potential therapeutic target for ALS.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by microglia-mediated neuroinflammation.
- The precise mechanisms driving this neuroinflammation in ALS are not fully understood.
Purpose of the Study:
- To investigate the role of MAPK/MAK/MRK overlapping kinase (MOK) in microglial immune responses relevant to ALS.
- To identify MOK's downstream effectors and its contribution to neuroinflammation in ALS.
Main Methods:
- Utilized cell-based assays and animal models of ALS.
- Investigated the interaction between MOK and bromodomain-containing protein 4 (Brd4).
- Assessed the impact of MOK inhibition on disease progression in ALS model mice.
Main Results:
- Identified MOK as a key regulator of inflammatory and type-I interferon responses in microglia.
- Discovered that MOK promotes phosphorylation of Brd4 at Ser492, enhancing its binding to cytokine gene promoters.
- Observed increased MOK levels in ALS spinal cords, particularly in microglia.
- Demonstrated that MOK inhibition in ALS model mice reduces microglial activation and ameliorates disease course.
Conclusions:
- MOK plays a significant role in ALS pathogenesis by driving detrimental microglial inflammation.
- MOK-mediated regulation of Brd4 is a critical pathway in ALS-associated neuroinflammation.
- Targeting MOK represents a potential therapeutic strategy for ALS and related neuroinflammatory conditions.
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