Abstract 17369: Sumoylation Regulates Nuclear Localization and Function of Zinc Finger Transcription Factor ZIC3
ZIC3, an X-linked zinc finger transcription factor, was the first identified gene involved in establishing normal left-right patterning in humans. Mutations in ZIC3 gene in patients cause heterotaxy, which includes complex congenital heart defects (CHDs), such as dextrocardia, transposition of the great arteries (TGA), double outlet right ventricle (DORV) and right aortic arch (AoA), and left-right axis defects in other organs. However, very little is known about how the function of ZIC3 protein is regulated. SUMO modification, or SUMOylation, is a process in which a special group of ubiquitin-like proteins (ULPs), small ubiquitin-like modifier (SUMO) proteins, are covalently attached to targets via a series of enzymatic reactions. We here reported that SUMOylation targeted human ZIC3 primarily on lysine residue 248, which was critical for the nuclear export of ZIC3. SUMO modification potentiated the repressive activity of ZIC3 on cardiac α-actin promoter, and the mutation of lysine 248 to arginine (K248R) abolished its repressive function. PIAS1, a SUMO E3 ligase, potently increased SUMOylation of ZIC3 on the canonical SUMO site of ZIC3 WT or non-canonical SUMO site(s) of K248R mutant via its RING domain. We further revealed that ZIC3 variants with mutations found in patients with congenital anomalies exhibited aberrant sumoylation activity, which at least partially accounted for cytoplasmic diffusion. Thus, the altered SUMOylation status of ZIC3 underpinned the developmental abnormalities associated with these ZIC3 mutants. The SUMO targeting consensus sequence in Zic3 is highly conserved in its paralogs and orthologs, pointing to SUMOylation as a general mechanism underlying the functional control of Zic proteins.
- © 2012 by American Heart Association, Inc.