The fifth element: a novel eIF2α kinase in microglia

Abstract

The cellular integrated stress response (ISR) is a central signaling pathway that tunes translation initiation in response to a wide range of cellular insults to promote cell survival. The critical node of this regulation involves the phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) by stress kinases. In this issue of EMBO reports, Wu et al (2023) report FAM69C as a novel eIF2α kinase that promotes ISR activation and stress granule (SG) assembly in microglia in response to oxidative stress. This work proposes a protective role for FAM69C and SGs in limiting damaging inflammatory responses commonly associated with neurodegenerative diseases.

Figure 1. Proposed model of the impact of FAM69C on the integrated stress response and inflammasome activation in aging‐related disorders

Microglia sense damage‐associated ATP released in the central nervous system. FAM69C is a brain‐specific serine/threonine kinase that phosphorylates eIF2α and acts as a signal facilitator for the HRI‐mediated integrated stress response (ISR) and stress granule (SG) formation upon exposure to oxidative stress and ATP (insert). In LPS‐primed fam69c ^+/+ microglia (left), exposure to ATP activates the ISR, which precludes the NRLP3 inflammasome activation and ASC speck formation. In contrast, in LPS‐primed fam69c ^−/− microglia (right), SG formation is reduced in favor of strong inflammasome activation.