An Essential Role for SHARPIN in the Regulation of Caspase 1 Activity in Sepsis

Madalina Viviana Nastase, Jinyang Zeng-Brouwers, Helena Frey, Louise Tzung Harn Hsieh, Chiara Poluzzi, Janet Beckmann, Nina Schroeder, Josef Pfeilschifter, Jaime Lopez-Mosqueda, Jan Mersmann, Fumiyo Ikeda, Renato V. Iozzo, Ivan Dikic, Liliana Schaefer

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Abstract

Sepsis is burdened by high mortality due to uncontrolled inflammatory response to pathogens. Increased caspase 1 activation causing maturation of IL1β/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, Il1β/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 IL1β/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 Il1β/18 and active caspase 1, and shortened survival. Inhibition of caspase 1 reduced levels of Il1β/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.

Original languageEnglish
Pages (from-to)1206-1220
Number of pages15
JournalAmerican Journal of Pathology
Volume186
Issue number5
DOIs
Publication statusPublished - May 1 2016
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Nastase, M. V., Zeng-Brouwers, J., Frey, H., Hsieh, L. T. H., Poluzzi, C., Beckmann, J., ... Schaefer, L. (2016). An Essential Role for SHARPIN in the Regulation of Caspase 1 Activity in Sepsis. American Journal of Pathology, 186(5), 1206-1220. https://doi.org/10.1016/j.ajpath.2015.12.026