Sumoylation regulates nuclear localization and function of zinc finger transcription factor ZIC3

Abstract

ZIC3, an X-linked zinc finger transcription factor, was the first identified gene involved in establishing normal left-right patterning in humans. Mutations in the Zic3 gene in patients cause heterotaxy, which includes congenital heart defects. However, very little is known about how the function of the ZIC3 protein is regulated. Sumoylation is a posttranslational modification process in which a group of small ubiquitin-like modifier (SUMO) proteins is covalently attached to targets via a series of enzymatic reactions. Here, we report for the first time that sumoylation targets human ZIC3 primarily on the consensus lysine residue K248, which is critical for the nuclear retention of ZIC3. Consequently, SUMO modification potentiates the repressive activity of ZIC3 on the promoter of its target gene cardiac α-actin, and the mutation of lysine 248 to arginine (K248R) abolishes its repressive function. We further revealed that ZIC3 variants with mutations found in human patients with congenital anomalies exhibit aberrant sumoylation activity, which at least partially accounts for their cytoplasmic diffusion. Improved sumoylation of human disease-associated ZIC3 variants reestablishes their nuclear occupancy in the presence of SUMO E3 ligase and SUMO-1. Thus, the altered sumoylation status of ZIC3 underpins 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. This study provides a potential therapeutic strategy to regain the normal subcellular distribution and function of ZIC3 mutants by restoring SUMO conjugation.

The WNT Signaling Pathway Contributes to Dectin-1-Dependent Inhibition of Toll-Like Receptor-Induced Inflammatory Signature

“…The SOCS family of genes is known to bring about ubiquitination-mediated degradation of target proteins such as STAT, thus downregulating IFN-␥ response (51,52). The PIAS family of proteins sumoylate several known immune modulators, thus relegating them to a new cellular location and resulting in a loss of function (53)(54)(55).…”

Review of X‐linked syndromes with arthrogryposis or early contractures—aid to diagnosis and pathway identification

“…Several of the mutations in ZIC3 disrupt the conserved C2H2 zinc finger motif while other mutations are proposed to alter its nuclear retention. Nuclear retention of Zic3, and thus its transcriptional activities, is regulated at least in part by sumoylation at residue K248 and individuals with congenital anomalies caused by ZIC3 mutations have aberrant sumoylation [Chen et al, ]. Mutations in mouse, Xenopus laevis and zebrafish ZIC3 homologues all show axial defects.…”

“…Mutations in mouse, Xenopus laevis and zebrafish ZIC3 homologues all show axial defects. Consistent with a role in early development, ZIC3 is highly expressed in neuroectoderm and mesoderm during gastrulation of mouse, chick, Xenopus and zebrafish embryos [Purandare et al, ; Cast et al, ; Chen et al, ].…”

Sumoylation Negatively Regulates CSR1-Dependent Prostate Cancer Cell Death

“…However, by using mutagenesis assay, we demonstrate that CSR1 is SUMOylated at K582 in prostate cancer cells and SUMOylation inhibits its tumor suppressor function, most likely by promoting ubiquitin-and proteasome-dependent degradation of CSR1. Several works have shown that SUMOylation could alter the intracellular localization of its target proteins [18,19], thus, we could not exclude the possibility that CSR1 SUMOylation might change its intracellular localization to affect its stability.…”