DeSUMOylation switches Kaiso from activator to repressor upon hyperosmotic stress

Abstract

Kaiso is a member of the BTB/POZ zinc finger family, which is involved in cancer progression, cell cycle control, apoptosis, and WNT signaling. Depending on promoter context, it may function as either a transcriptional repressor or activator. Previous studies found that Kaiso might be SUMOylated due to heat shock, but the biological significance of Kaiso SUMOylation is unclear. Here, we find that K42 is the only amino acid within Kaiso that is modified with SUMO. Kaiso is monoSUMOylated at lysine 42 in cell lines of kidney origin under normal physiological conditions. SUMOylated Kaiso can activate transcription from exogenous methylated promoters, wherein the deSUMOylated form of the protein kept the ability to be a repressor. Rapid Kaiso deSUMOylation occurs in response to hyperosmotic stress and is reversible upon return to an isotonic environment. DeSUMOylation occurs within minutes in HEK293 cells treated with 100 mM NaCl and relaxes in 3 h even in a salt-containing medium. Genomic editing of Kaiso by conversion of K42 into R42 (K42R) in HEK293 cells that resulted in fully deSUMOylated endogenous protein led to misregulation of genes associated with ion transport, blood pressure, and the immune response. TRIM25 was significantly repressed in two K42R HEK293 clones. By a series of rescue experiments with K42R and KO HEK293 cells, we show that TRIM25 is a direct transcriptional target for Kaiso. In the absence of Kaiso, the level of TRIM25 is insensitive to hyperosmotic stress. Extending our observations to animal models, we show that in response to a high salt diet, Kaiso knockout mice are characterized by significantly higher blood pressure increases when compared to wild-type animals. Thus, we propose a novel biological role for Kaiso in the regulation of homeostasis.

ZBTB33 (Kaiso) methylated binding sites are associated with primed heterochromatin

“…Interestingly, ZBTB33 is also able to function as a methyl-dependent activator [43]. A more recent work by Zhenilo et al suggests that SUMOylation in ZBTB33 BTB/POZ protein-protein interaction domain may switch ZBTB33 from a gene repressor to an activator [44].…”

Kaiso-induced intestinal inflammation is preceded by diminished E-cadherin expression and intestinal integrity

“…Kaiso functions both as a transcription repressor, and as an activator, depending on the tissue microenvironment, but its activity is also regulated by post-translational modifications (e.g. phosphorylation, SUMOylation) [26, 27]. While our study was the first to implicate Kaiso in intestinal inflammation, the incipient stages of this process have not yet been elucidated.…”

Dancing from bottoms up – Roles of the POZ-ZF transcription factor Kaiso in Cancer

“…A recent study by Zhenilo et al investigated the effect of post translational modifications on Kaiso’s transcriptional activity [26] and found that covalent linkage of small ubiquitin-like modifier (SUMO) polypeptides functioned as a molecular switch to regulate Kaiso’s function as an activator or repressor [26]. When SUMOylated, Kaiso acted as an activator but when deSUMOylated, Kaiso acted as a repressor (Figure 1).…”

“…When SUMOylated, Kaiso acted as an activator but when deSUMOylated, Kaiso acted as a repressor (Figure 1). Using HEK293 cells, the authors demonstrated that Kaiso is SUMOylated under normal conditions at lysine 93 (K93); however, under hyperosmotic stress, Kaiso was found to be deSUMOylated [26]. This was the first study to elucidate a role for post-translational modifications on Kaiso function and indicates that further work is needed to examine other mechanisms (e.g.…”