The human disease-associated gene ZNFX1 controls inflammation through inhibition of the NLRP3 inflammasome, 2024, Huang et al

[chillier]

Abstract​

Inherited deficiency of zinc finger NFX1-type containing 1 (ZNFX1), a dsRNA virus sensor, is associated with severe familial immunodeficiency, multisystem inflammatory disease, increased susceptibility to viruses, and early mortality. However, limited treatments for patients with pathological variants of ZNFX1 exist due to an incomplete understanding of the diseases resulting from ZNFX1 mutations. Here, we demonstrate that ZNFX1 specifically inhibits the activation of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome in response to NLRP3 activators both in vitro and in vivo. ZNFX1 retains NLRP3 in the cytoplasm and prevents its accumulation in the TGN38 + /TGN46+ vesicles in the resting state. Upon NLRP3 inflammasome activation, ZNFX1 is cleaved by caspase-1, establishing a feed-forward loop that promotes NLRP3 accumulation in the trans-Golgi network (TGN) and amplifies the activity of the downstream cascade. Expression of wild-type ZNFX1, but not of ZNFX1 with human pathogenic mutations, rescues the impairment of NLRP3 inflammasome inhibition. Our findings reveal a dual role of ZNFX1 in virus sensing and suppression of inflammation, which may become valuable for the development of treatments for ZNFX1 mutation-related diseases.

Link: https://www.embopress.org/doi/full/10.1038/s44318-024-00236-9

 

[chillier]

ZNFX1 is a decodeME candidate with eQTL data supporting its levels are increased in ME/CFS.

 

[hotblack]

ZNFX1 is a decodeME candidate with eQTL data supporting its levels are increased in ME/CFS.

And increased ZNFX1 equates to decreased inflammation or inflammatory signals? So is this something ‘anti-inflammatory’ popping up again?

NLRP3 is apparently expressed predominantly in macrophages. And more ZNFX1 would suppress/inhibit activation here?

 

[LizWorthey]

For their mouse work: When folks mention an effect for a particular mouse model, you can generally find info on the phenotype/symptoms for the model here: https://www.informatics.jax.org/marker/phenotypes/MGI:2138982. That link is for this gene. In this case, there are IMPC mice where they knocked out (removed the functioning version of) the gene and they see no immune defects, which they would have looked for.. And there are the mice from this group, which show a strong immune phenotype. With the mutations introduced at exon5 and exon3 in each model a similar effect might be expected (would need to dig in to that more to be sure). One difference is the background strain. The first (no immune effect) is C57BL/6J and the other (immune effect) is C57BL/6NJ. Looks like C57BL/6J may boost immune phenotypes (please an immunologist weigh in). You can also look here: https://www.proteinatlas.org/ENSG00000162711-NLRP3/single+cell to see where the genes mentioned transcripts are expressed. This gene is seen in a few different cell types, which I think make it more interesting. Just adding this to provide some additional perhaps useful context.