A novel CARD containing splice-isoform of CIITA regulates nitric oxide synthesis in dendritic cells

Abstract

MHC class II expression is controlled mainly at transcriptional level by class II transactivator (CIITA), which is a non-DNA binding coactivator and serves as a master control factor for MHC class II genes expression. Here, we describe the function of a novel splice-isoform of CIITA, DC-expressed caspase inhibitory isoform of CIITA (or DC-CASPIC), and we show that the expression of DC-CASPIC in DC is upregulated upon lipopolysaccharides (LPS) induction. DC-CASPIC localizes to mitochondria, and protein-protein interaction study demonstrates that DC-CASPIC interacts with caspases and inhibits its activity in DC. Consistently, DC-CASPIC suppresses caspases-induced degradation of nitric oxide synthase-2 (NOS2) and subsequently promotes the synthesis of nitric oxide (NO). NO is an essential regulatory molecule that modulates the capability of DC in stimulating T cell proliferation/activation in vitro; hence, overexpression of DC-CASPIC in DC enhances this stimulation. Collectively, our findings reveal that DC-CASPIC is a key molecule that regulates caspases activity and NO synthesis in DC.

Caspase-2 associates with FAN through direct interaction and overlapping functionality

“…Interestingly, dendritic cells can produce a CARD-containing splice-isoform of CIITA, which has the ability to inhibit caspase-mediated degradation of nitric oxide synthase-2 or, conversely, promote the production of nitric oxide (NO). This, in turn, regulates the capability of dendritic cells to trigger T-cell activation/proliferation (Huang et al, 2010). In our study, while analyzing total protein levels from APCs, we observed a concomitant increase in MHC II following a loss of caspase-2.…”