PSMA7 Directly Interacts with NOD1 and Regulates its Function

Abstract

Background/Aims: Recent reports showed that proteasome subunit alpha type-7 (PSMA7) was overexpressed in colorectal cancer. To investigate the mechanism of PSMA7 in promotion of colorectal cancer, we screened for its interaction partners. Methods and Results: This study found that PSMA7 associated with nucleotide-binding oligomerization domain-containing protein 1 (NOD1) by yeast two-hybrid screening, co-immunoprecipitation (IP), and GST-pull down assay. As shown by Western blotting and ubiquitin assay, PSMA7 downregulated the expression of NOD1 in a proteasome-dependent manner. Overexpression of PSMA7 in HCT116 cells resulted in an inhibition of NOD1-mediated apoptosis and NF-κB activation, whereas knockdown of PSMA7 by RNA interference enhanced NOD1 activity. Conclusion: Our data suggest that PSMA7 is a negative regulator of the NOD1, and may promote tumor growth by its inhibitory role on NOD1.

Columbianadin Suppresses Lipopolysaccharide (LPS)-Induced Inflammation and Apoptosis through the NOD1 Pathway

“…PSMA7 [26] has recently been shown to reduce NOD1 activation and inhibit apoptosis induction. The authors hold the opinion that there are extensive cross-talks between apoptosis and the NF-κB pathway.…”

The transcription levels and prognostic values of seven proteasome alpha subunits in human cancers

“…Although PMSA7 knockdown in colorectal cancer cell line RKO showed no impact on proliferation or cell cycle, depletion of PSMA7 was demonstrated to significantly suppress tumor formation in vitro and in vivo , as well as inhibit RKO cell invasion and migration [4]. NOD1 is regulated by PSMA7 in a proteasome-dependent manner, and overexpression of PSMA7 inhibits NOD1-mediated colorectal cancer cell apoptosis [64]. The non-small cell lung cancer cell lines A549 and NCI-H460 treated with PSMA1 siRNA showed a loss of the chymotrypsin-like activity of proteasome and a significant decrease in homologous recombination-mediated repair of I-SceI-induced DNA double strand breaks [6].…”

Understanding the regulation of pattern recognition receptors in inflammatory diseases – a ‘Nod’ in the right direction

“…The proposed mechanism of negative regulation for RNF34 and PSMA7 is by way of the ubiquitin/proteasome pathway, whereby NOD1 is K48‐ubiquitinated, thereby targeting it to the proteasome for degradation by proteolysis. This mechanism was supported by inhibition studies, whereby the inhibitory effects of RNF34 and PSMA7 on NOD1 activity were significantly impeded by treatment with a proteasome inhibitor (MG132) or small interfering RNA knockdown of PSMA7, respectively. RNF34 and PSMA7 expression studies have yet to be carried out to establish whether these proteins are directly linked to chronic inflammatory disease.…”

“…The ring finger protein 34 (RNF34) E3 ubiquitin ligase and the 20S proteasome subunit α 7 (PSMA7), have both been proposed as novel negative regulators of NOD1 signalling. In vitro studies have uncovered NOD1 activity to be indirectly proportional to both RNF34 and PSMA7 levels. The proposed mechanism of negative regulation for RNF34 and PSMA7 is by way of the ubiquitin/proteasome pathway, whereby NOD1 is K48‐ubiquitinated, thereby targeting it to the proteasome for degradation by proteolysis.…”