Zinc finger HIT domain-containing protein 3 (ZNHIT3)

Zinc finger HIT domain-containing protein 3 (ZNHIT3) is an evolutionarily conserved protein characterized by an N-terminal zinc finger HIT domain, a novel protein–protein interaction motif that coordinates two zinc ions in a treble clef fold. ZNHIT3 is not a classical enzyme, transporter, or receptor, but is a nuclear, predominantly nucleolar, protein essential for snoRNP (small nucleolar ribonucleoprotein) assembly and ribosome biogenesis. It is required for the correct assembly of box C/D snoRNPs and maintains steady-state levels of key assembly factors such as NUFIP1 and PIH1D1. Loss-of-function or destabilizing mutations in ZNHIT3 result in reduced snoRNP assembly, ribosome synthesis defects, impaired cell proliferation, and can cause PEHO syndrome—a severe, typically postnatal-onset neurodevelopmental disorder, with expanding evidence for prenatal lethality in some cases. Early data also suggested it may act as a transcriptional coactivator for nuclear hormone receptors such as HNF-4α and thyroid hormone receptor, although this remains less well characterized. ZNHIT3 is not known to bind directly to DNA or histone tails, but affects transcription and ribosome function through its role in assembling functional RNP complexes. No specific drugs or targeted therapeutics are reported against ZNHIT3.

Other names

TRIP3TR-interacting protein 3Hit1HNF-4α coactivatorThyroid hormone receptor interactor 3Thyroid receptor-interacting protein 3PEHOzinc finger, HIT type 3