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The downregulation of melatonin receptor 1A (MTNR1A) is associated with a range of pathological conditions, including membranous nephropathy. Knowledge of the mechanism underlying MTNR1A expression has been limited to the transcriptional regulation level. Here, RNA interference screening in human kidney cells revealed that heterogeneous nuclear ribonucleoprotein L (hnRNPL) upregulated MTNR1A RNA post‐transcriptionally. hnRNPL knockdown or overexpression led to increased or decreased levels of cyclic adenosine monophosphate‐responsive element‐binding protein phosphorylation, respectively. Molecular studies showed that cytoplasmic hnRNPL exerts a stabilizing effect on the MTNR1A transcript through CA‐repeat elements in its coding region. Further studies revealed that the interaction between hnRNPL and MTNR1A serves to protect MNTR1A RNA degradation by the exosome component 10 protein. MTNR1A, but not hnRNPL, displays a diurnal rhythm in mouse kidneys. Enhanced levels of MTNR1A recorded at midnight correlated with robust binding activity between cytoplasmic hnRNPL and the MTNR1A transcript. Both hnRNPL and MTNR1A were decreased in the cytoplasm of tubular epithelial cells from experimental membranous nephropathy kidneys, supporting their clinical relevance. Collectively, our data identified cytoplasmic hnRNPL as a novel player in the upregulation of MTNR1A expression in renal tubular epithelial cells, and as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Infection is a known cause of abdominal aortic aneurysm (AAA), and matrix metalloproteases‐2 (MMP‐2) secreted by vascular smooth muscle cells (SMCs) plays a key role in the structural disruption of the middle layer of the arteries during AAA progression. The periodontal pathogen Porphyromonas gingivalis is highly associated with the progression of periodontitis. GroEL protein of periodontal pathogens is an important virulence factor that can invade the body through either the bloodstream or digestive tract and is associated with numerous systemic diseases. Although P. gingivalis aggravates AAA by increasing the expression of MMP‐2 in animal studies, the molecular mechanism through which P. gingivalis regulates the expression of MMP‐2 is still unknown and requires further investigation.In this study, we first confirmed through animal experiments that P. gingivalis GroEL promotes MMP‐2 secretion from vascular SMCs, thereby aggravating Ang II‐induced aortic remodeling and AAA formation. In addition, rat vascular SMCs and A7r5 cells were used to investigate the underlying mechanisms in vitro. The results demonstrated that GroEL can promote the interaction between the K639 site of MMP‐2 and SUMO‐1, leading to MMP‐2 SUMOylation, which inhibits the reoccurrence of non–K639‐mediated monoubiquitylation. Hence, the monoubiquitylation‐mediated lysosomal degradation of MMP‐2 is inhibited, consequently promoting MMP‐2 stability and production. SUMOylation may facilitate intra‐endoplasmic reticulum (ER) and Golgi trafficking of MMP‐2, thereby enhancing its transport capacity. In conclusion, this is the first report demonstrating the presence of a novel posttranslational modification, SUMOylation, in the MMP family, suggesting that P. gingivalis GroEL may exacerbate AAA formation by increasing MMP‐2 production through SUMOylation in vascular SMCs. This study also provides a novel perspective on the role of SUMOylation in MMP‐2–induced systemic diseases. [ABSTRACT FROM AUTHOR]

XRCC1 is an essential scaffold protein for base excision repair (BER) and helps to maintain genomic stability. XRCC1 has been indicated as a substrate for small ubiquitin-like modifier modification (SUMOylation); however, how XRCC1 SUMOylation is regulated in cells and how SUMOylated XRCC1 regulates BER activity are not well understood. Here, we show that SUMOylation of XRCC1 is regulated in cells under methyl-methanesulfonate (MMS) treatment and facilitates BER. Poly(ADP-ribose) polymerase 1 (PARP1) is activated by MMS immediately and synthesizes poly(ADP-ribose) (PAR), which in turn promotes recruitment of SUMO E3 TOPORS to XRCC1 and facilitates XRCC1 SUMOylation. A SUMOylation-defective mutant of XRCC1 had lower binding activity for DNA polymerase beta (POLB) and was linked to a lower capacity for repair of MMS-induced DNA damages. Our study therefore identified a pathway in which DNA damage-induced poly(ADP-ribosyl)ation (PARylation) promotes SUMOylation of XRCC1, which leads to more efficient recruitment of POLB to complete BER.

Constitutive activation of the transcription factor TCF4 activity by mutated APC or beta-catenin contributes to cell neoplastic transformation. While numerous proteins were identified to activate TCF4-dependent activity via beta-catenin interaction, little is known about factors directly acting on TCF4. Here we report that Daxx binds to TCF4 and potentiates beta-catenin/TCF4-mediated transcriptional activation and target gene expression. Binding studies revealed that Daxx-TCF4 interaction is through the C-terminal domain of Daxx and TCF4 segment containing amino acid residue 269-327. Alteration of Daxx levels in cells by overexpression or RNA interference resulted in an increase or decrease of the beta-catenin/TCF4-dependent transactivation activity and target gene expression, respectively. Furthermore, TCF4-(269-327) segment acts as a dominantly negative mutant by blocking Daxx-TCF4 interaction and TCF4-mediated transactivation potential. Together, our results suggest that Daxx functions as a positive coregulator in modulating the beta-catenin/TCF4-dependent transcriptional potential via TCF4 interaction.