These authors contributed equally.
Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β
Article first published online: 10 AUG 2012
© 2012 Wiley Periodicals, Inc.
Volume 34, Issue 1, pages 122–131, January 2013
How to Cite
Luksch, H., Romanowski, M. J., Chara, O., Tüngler, V., Caffarena, E. R., Heymann, M. C., Lohse, P., Aksentijevich, I., Remmers, E. F., Flecks, S., Quoos, N., Gramatté, J., Petzold, C., Hofmann, S. R., Winkler, S., Pessler, F., Kallinich, T., Ganser, G., Nimtz-Talaska, A., Baumann, U., Runde, V., Grimbacher, B., Birmelin, J., Gahr, M., Roesler, J. and Rösen-Wolff, A. (2013), Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β. Hum. Mutat., 34: 122–131. doi: 10.1002/humu.22169
Communicated by David N. Cooper
Contract grant sponsors: German Research Foundation (DFG, KFO 249, TP1, RO/471-11 and TP2, HO 4510/1-1); Federal Ministry of Education and Research (PID-NET, Project A4); Medical faculty of the University of Technology Dresden, MeDDrive33 (08/09): 60.153 to S.W., Germany; Marie Curie International Reintegration Grant, # 224894 to F.P., European Union.
- Issue published online: 20 DEC 2012
- Article first published online: 10 AUG 2012
- Accepted manuscript online: 25 JUL 2012 01:41PM EST
- Manuscript Accepted: 11 JUL 2012
- Manuscript Received: 17 FEB 2012
- German Research Foundation. Grant Numbers: RO/471-11, HO 4510/1-1
- Federal Ministry of Education and Research
- Medical faculty of the University of Technology Dresden, MeDDrive33. Grant Number: (08/09): 60.153
- Marie Curie International Reintegration. Grant Number: # 224894
Caspase-1 (Interleukin-1 Converting Enzyme, ICE) is a proinflammatory enzyme that plays pivotal roles in innate immunity and many inflammatory conditions such as periodic fever syndromes and gout. Inflammation is often mediated by enzymatic activation of interleukin (IL)-1β and IL-18. We detected seven naturally occurring human CASP1 variants with different effects on protein structure, expression, and enzymatic activity. Most mutations destabilized the caspase-1 dimer interface as revealed by crystal structure analysis and homology modeling followed by molecular dynamics simulations. All variants demonstrated decreased or absent enzymatic and IL-1β releasing activity in vitro, in a cell transfection model, and as low as 25% of normal ex vivo in a whole blood assay of samples taken from subjects with variant CASP1, a subset of whom suffered from unclassified autoinflammation. We conclude that decreased enzymatic activity of caspase-1 is compatible with normal life and does not prevent moderate and severe autoinflammation.