CBL-b regulates the protein stability of lupus susceptibility gene PBX1 2379

Abstract Description Pre-B cell leukemia homeobox1 (PBX1) regulates gene expression by controlling chromatin accessibility. The expression of PBX1-D, a dominant negative splice isoform in CD4+ T cells, promotes lupus phenotypes. Among CD4+ T cells, PBX1 and PBX1-D are preferentially expressed in Treg cells among CD4+ T cells at the transcript and protein levels, and we have shown that Pbx1-deficiency altered Treg maintenance and function. PBX1-D protein is less stable than the normal isoform, PBX1-B, and it is degraded through the ubiquitin-proteasome-dependent pathway. Interestingly, CBL-b, E3 ubiquitin ligase functioning as a negative regulator of T cell activation, is downregulated in SLE CD4+ T cells. Here we showed that CBL-b is highly expressed in Treg cells and that it directly interacts with PBX1 and leads to Ub-mediated protein degradation. Cbl-b overexpression significantly decreased either PBX1-B or PBX1-D protein. In addition, mass spectrometry has identified TRIM21, another E3 Ub ligase, as a PBX1 binding partner with a weaker binding to PBX1-D. The relative abundance of the PBX1-D isoform in Tregs therefore integrates its interaction with E3 Ub ligases and their level of expression. Additional studies are on-going to further delineate the molecules involved in PBX1 protein expression in SLE T cells. Funding Sources This work was supported by National Institutes of Health Grants AI045050 Topic Categories Basic Autoimmunity (BA)