Regulation of inflammatory signaling by TBL1/TBLR1

Abstract

Dysregulation of inflammatory signaling has been implicated in the development of human diseases. Nuclear factor κB (NF-κB) plays a key role in regulating inflammatory signaling through controlling the NF-κB target genes. Recently, the formation of NF-κB and transducin β-like protein (TBL1) complex upon tumor necrosis factor-alpha (TNF-α) has been reported; however, little is known about how the corepressor TBL1 activates NF-κB function. Here, we show that both TBL1 and its related protein (TBLR1) are SUMOylated in a NF-κB mediated inflammatory signaling-dependent manner, and this modification is selectively reversed by SUMO-specific protease I (SENP1). SUMOylation of TBL1-TBLR1 increased the expression of NF-κB target genes by interacting with NF-κB and consequently led to activation of NF-κB-mediated inflammation. Conversely, SENP1 inhibited SUMOylation of TBL1-TBLR1, leading to reduction of NF-κB-mediated transcription. Finally, knockdown of TBL1 greatly impaired the production of interleukin (IL)-1beta, IL-6, and IL-8 in androgen-independent prostate cancer, PC-3 cells. Thus, our data reveal a mechanism for regulation of NF-κB mediated inflammation signal via the reversible SUMOylation of TBL1 and TBLR1.