| First Author | Nastase MV | Year | 2016 |
| Journal | Am J Pathol | Volume | 186 |
| Issue | 5 | Pages | 1206-20 |
| PubMed ID | 26968342 | Mgi Jnum | J:231908 |
| Mgi Id | MGI:5775490 | Doi | 10.1016/j.ajpath.2015.12.026 |
| Citation | Nastase MV, et al. (2016) An Essential Role for SHARPIN in the Regulation of Caspase 1 Activity in Sepsis. Am J Pathol 186(5):1206-20 |
| abstractText | Sepsis is burdened by high mortality due to uncontrolled inflammatory response to pathogens. Increased caspase 1 activation causing maturation of IL1beta/18 remains a therapeutic challenge in sepsis. SHARPIN (shank-associated regulator of G-protein signaling homology domain-interacting protein), a component of the LUBAC (linear ubiquitin chain-assembly complex), regulates inflammation, with unknown effects on caspase 1 activation. Mice lacking Casp1, Casp11, or both in a Sharpin-deficient background were generated, exposed to lipopolysaccharide-induced endotoxemia, and injected with caspase 1 inhibitor. We monitored survival, Il1beta/18, and caspase 1/11 levels in plasma and organs and deciphered mechanisms of SHARPIN-dependent caspase 1 inhibition. A correlation between LUBAC and active caspase 1 was found in blood mononuclear cells from septic patients. SHARPIN bound caspase 1 and disrupted p20/p10 dimer formation, the last step of caspase 1 processing, thereby inhibiting enzyme activation and maturation of IL1beta/18 in a LUBAC-independent manner. In septic patients, LUBAC-independent decline in SHARPIN correlated with enhancement of active caspase 1 in circulating mononuclear cells. Septic Sharpin-deficient mice displayed enrichment in mature Il1beta/18 and active caspase 1, and shortened survival. Inhibition of caspase 1 reduced levels of Il1beta/18 and splenic cell death, and prolonged survival in septic Sharpin-deficient mice. Our findings identify SHARPIN as a potent in vivo caspase 1 inhibitor and propose the caspase 1-SHARPIN interaction as a target in sepsis. |
