Control of Smad7 Stability by Competition between Acetylation and Ubiquitination

Abstract

Smad proteins regulate gene expression in response to TGFbeta signaling. Here we present evidence that Smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of Smad7 on two lysine residues in its N terminus. Acetylation or mutation of these lysine residues stabilizes Smad7 and protects it from TGFbeta-induced degradation. Furthermore, we demonstrate that the acetylated residues in Smad7 also are targeted by ubiquitination and that acetylation of these lysine residues prevents subsequent ubiquitination. Specifically, acetylation of Smad7 protects it against ubiquitination and degradation mediated by the ubiquitin ligase Smurf1. Thus, our data suggest that competition between ubiquitination and acetylation of overlapping lysine residues constitutes a novel mechanism to regulate protein stability.

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

“…These functional differences could be due to differential association with other proteins, such as gene-specific transcription factors, and variations in substrate specificity between these two histone acetyltransferases. The latter case is demonstrated in an earlier study indicating that Smad7, a TGF-β response gene that negatively regulates TGF-β signaling, is acetylated by p300 and becomes stabilized and protected from proteasome (Smurf-1)-mediated degradation (Gronroos et al, 2002). Conversely, histone deacetylases (HDAC) interact with Smad7 and promotes the degradation of Smad7 protein (Simonsson et al, 2005).…”

Smad3 is acetylated by p300/CBP to regulate its transactivation activity

“…First, acetylation may stabilize the Smad3 protein. Recently, Gronroos et al (2002) have shown that the acetylation of Smad7 protects it against ubiquitination and degradation mediated by the ubiquitin ligase Smurf1. As shown in Figure 5a, expression level of K378R mutant is almost same.…”

Enforced Expression of NUP98-HOXA9 in Human CD34+ Cells Enhances Stem Cell Proliferation

“…p53 and its structural and functional homologue p73 are protected from ubiquitination by such an acetylation process (44,45). Competition between ubiquitination and acetylation of overlapping lysine residues constitutes a novel mechanism regulating protein stability (46).…”