The endoribonuclease N4BP1 prevents psoriasis by controlling both keratinocytes proliferation and neutrophil infiltration

Abstract

Psoriasis is a common chronic skin disease, characterized by abnormal interplay between hyperproliferative epidermal keratinocytes and self-reactive immune cells with not fully addressed molecular mechanism. N4BP1 (NEDD4-binding protein 1) is considered as an immune regulator for a long time but its physiological role is not determined yet. Here, we found that the expression of N4BP1 in skin was highest among all 54 tested tissues, and its expression was further upregulated in psoriatic skin. N4BP1-deficient mice exhibited normal grossly, but developed severe and prolonged IMQ-induced psoriasis-like disease comparing to controls. N4BP1 mainly expressed in keratinocytes and located on nucleus. Up- but not downregulated genes in N4BP1-deficient skin were specifically enriched in keratinocyte proliferation and differentiation. The proliferation of N4BP1-deficient primary keratinocytes was faster compared to that of controls. The upregulated genes upon ablation of N4BP1 were highly enriched in targets of AP-1 transcription factor. Knocking out N4BP1 resulted in upregulation of JunB and FosB, and conversely, overexpression of N4BP1 greatly reduced their expression. Furthermore, N4BP1 binds with JunB and FosB encoding mRNAs and greatly reduces their stability. In addition, with a high expression in neutrophils, N4BP1 limits survival of neutrophils in blood and infiltration of neutrophils in psoriatic skin by targeting CXCL1, CCL20, and S100A8. These findings demonstrate that N4BP1 controls the proper function of keratinocytes and neutrophils by negatively regulating JunB, FosB, and CXCL1, respectively, and that is critical for psoriasis prevention.

Porcine Reproductive and Respiratory Syndrome Virus Adapts Antiviral Innate Immunity via Manipulating MALT1

“…In this study, MCPIP1 and N4BP1 were confirmed to inhibit PRRSV replication, relying on their RNase activity. Both RNases belong to the Zc3h12a-like NYN domain subfamily of endoribonucleases and harbor a similar PIN-like domain with RNase activity ( 10 ). MCPIP1 is a spectrum antiviral RNase against various viruses, like HIV-1, by degrading viral mRNA ( 11 ).…”

“…Monocyte chemotactic protein-induced protein (MCPIP1), or Zc3h12a or Regnase-1, belongs to the Zc3h12a-like NYN domain subfamily of endoribonucleases. All members of the Zc3h12a-like RNase family have a similar PilT N terminus (PIN)-like domain with RNase activity, involved in antiviral immunity ( 10 ). MCPIP1 is a broad-spectrum antiviral protein, suppressing infection of HIV ( 11 ) and many other viruses.…”

N4BP1 mediates RAM domain‐dependent notch signaling turnover during neocortical development

“…As previous studies have shown that N4BP1 was predominantly located in the nucleolus (Sharma et al , 2010; Gou et al , 2021), we evaluated the distribution of N4BP1 in the nucleus and cytoplasm. In the E14.5 brain, E18.5 dorsal telencephalon, cultured NPCs, and N1E‐115 cells, N4BP1 was distributed mainly in the cytoplasm, and few in the nucleus.…”

Alendronate augments lipid A‑induced IL‑1β release by ASC‑deficient RAW264 cells via AP‑1 activation

“…NEDD4-binding protein 1 (N4BP1) is a nuclear RNase that degrades viral mRNA species in macrophages and primary T cells (23). N4BP1 also inhibits the production of proinflammatory cytokines and chemokines by inactivating AP-1 and NF-κB (22,24). The cleavage of N4BP1 by caspase-8 upregulates TLR4 ligand-induced cytokine production in mice, suggesting that ALN may degrade N4BP1 through the activation of caspase-8 (8).…”