MAPK/MAK/MRK overlapping kinase (MOK) controls microglial inflammatory/type-I IFN responses via Brd4 and is involved in ALS

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 unknown physiological substrate/s, displays an immune-related function, namely by controlling inflammatory and type-I IFN responses in microglia which result neurotoxic to primary motor neurons. Moreover, we uncover the epigenetic reader bromodomain-containing protein 4 (Brd4) as the first molecule regulated by MOK, by promoting Ser492-phospho-Brd4 levels. We further demonstrate that MOK regulates Brd4 functions by supporting Brd4 binding to cytokine gene promoters, therefore enabling innate immune responses. Remarkably, we show that MOK levels are increased in ALS spinal cord, particularly in microglial cells, and that administration of a chemical MOK-inhibitor to ALS model mice can suppress microglial activation and delay disease onset, pointing to a pathophysiological role of MOK kinase in ALS and neuroinflammation.