40 / 2024-10-01 17:00:31

De novo assembly of nuclear stress bodies restrain acute inflammatory responses

Nuclear stress bodies,SatⅢ,acute inflammatory responses,NFIL3,membrane-less organelles

Mammalian cells activate diverse defense mechanisms in response to stresses. Nuclear

stress bodies (nSBs) are transient membrane-less organelles in primates that only

present in sensing severe stresses. Little is known on how their formation contributes

to cellular homeostasis or whether nSBs have any physiopathological roles. Here, we

report that nSB components, including Satellite ⅢI (SatⅢ) DNAs, SatⅢ RNAs (the

hall marker of nSBs) and 30 proteins, are assembled into a well-organized structure

within 3 hours in living cells. Remarkably, the activated SatⅢ heterochromatin loci

rapidly expand, resulting in adjacent gene activation, including the transcription

suppressor NFIL3 known to dampen proinflammatory cytokine production. Upon

stresses, NFIL3 loci were found within or close to nSB territory due to SatⅢ locus

expansion, which enhances NFIL3 chromatin accessibility and makes NFIL3 promoters

spatially more accessible to transcription factors newly recruited to nSBs. Human

peripheral blood mononuclear cell (PBMC)-derived macrophages under heat shock and

LPS stresses exhibited increased expression of SatⅢ and NFIL3, the latter of which

prevents the excessive expression of key inflammatory cytokines. Importantly, NFIL3

expression positively correlates with SatⅢ activation in PBMCs from septic patients,

which appears to be beneficial for patient survival. These findings unveil an unexpected

role of the highly organized nSBs in shaping local gene organization upon stresses, and

highlight a crucial role of nSBs in restraining acute inflammatory responses.