Evolution of Caspase‐1 Inhibitors


CARD only protein 1 (COP1), inhibitory caspase recruitment domain (INCA) and ICEBERG are caspase recruitment domain (CARD)‐only proteins that inhibit the activation of cysteine‐dependent ASPartyl‐specific proteASE (caspase)‐1 or CASP‐1. Although CASP‐1 is widespread in vertebrates, CASP‐1 inhibitors are exclusively found in primates. The most ancient CASP‐1 inhibitor was found in the genome of a tree shrew, an ancestor of primates. The inhibitors are mapped in tandem at human chromosome 11 and their origin is directly and indirectly related to CASP‐1 gene duplications. Different stop codons arose in the duplicated copies just upstream of the catalytic domain of CASP‐1 generating CARD‐only proteins. In this review we discuss the most recent findings regarding the evolution of both caspases and their inhibitors.

Key concepts

  • COP, INCA and ICEBERG are CASP‐1 inhibitors.

  • COP, INCA and ICEBERG arose directly or indirectly from CASP‐1 duplications.

  • Procaspase‐1 contains a CARD and peptidase C14 domain, but the inhibitors contain only the CARD domain.

  • Stop codons upstream of the peptidase C14 domain where important for the generation of CASP‐1 inhibitors.

Keywords: caspase‐1; inhibitors; COP; INCA; ICEBERG; gene duplication

Figure 1.

Schematic representation of genomic duplications generating CASP‐1 inhibitors. ‘Ancient genomic’ represents the organization of genomic region before the duplication of CASP‐1. Numbers represent chronological order of genomic duplications originating the CASP‐1 inhibitors. ‘Current genomic’ represents the genomic organization of CASP‐1 and its inhibitors found in the human genome sequence (hg18). Yellow rectangles represent the genomic transcribed region of CASP‐1 inhibitors.

Figure 2.

Exon/intron organization of CASP‐1 and its inhibitors. (a) Representation of CASP‐1 genomic region (coding exons) and a known CASP‐1 transcript. (b) Representation of CASP‐1 inhibitors genomic regions and their transcripts. Black rectangles represent the genomic regions homologous to known exons in the CASP‐1 gene. ‘Known transcript’ represents a consensus transcript found for each one of genes.



Chowdhury I, Tharakan B and Bhat GK (2008) Caspases—an update. Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology 151: 10–27.

da Cunha JP, Galante PA and de Souza SJ (2008) Different evolutionary strategies for the origin of caspase‐1 inhibitors. Journal of Molecular Evolution 66: 591–597.

Eckhart L, Ballaun C, Hermann M et al. (2008) Identification of novel mammalian caspases reveals an important role of gene loss in shaping the human caspase repertoire. Molecular Biology and Evolution 25: 831–841.

Fuentes‐Prior P and Salvesen GS (2004) The protein structures that shape caspase activity, specificity, activation and inhibition. The Biochemical Journal 384: 201–232.

Humke EW, Shriver SK, Starovasnik MA et al. (2000) ICEBERG: a novel inhibitor of interleukin‐1beta generation. Cell 103: 99–111.

Kersse K, Vanden Berghe T, Lamkanfi M and Vandenabeele P (2007) A phylogenetic and functional overview of inflammatory caspases and caspase‐1‐related CARD‐only proteins. Biochemical Society Transactions 35: 1508–1511.

Koonin EV and Aravind L (2002) Origin and evolution of eukaryotic apoptosis: the bacterial connection. Cell Death and Differentiation 9: 394–404.

Lamkanfi M, Denecker G, Kalai M et al. (2004) INCA, a novel human caspase recruitment domain protein that inhibits interleukin‐1 beta generation. The Journal of Biological Chemistry 279: 51729–51738.

Lee SH, Stehlik C and Reed JC (2001) Cop, a caspase recruitment domain‐containing protein and inhibitor of caspase‐1 activation processing. The Journal of Biological Chemistry 276: 34495–34500.

Salvesen GS and Dixit VM (1999) Caspase activation: the induced‐proximity model. Proceedings of the National Academy of Sciences of the USA 96: 10964–10967.

Wang X, Narayanan M, Bruey JM et al. (2006) Protective role of Cop in Rip2/caspase‐1/caspase‐4‐mediated HeLa cell death. Biochimica et Biophysica Acta 1762: 742–754.

Further Reading

Degterev A and Yuan J (2008) Expansion and evolution of cell death programmes. Nature Reviews Molecular Cell Biology 9: 378–390.

Deponte M (2008) Programmed cell death in protists. Biochimica et Biophysica Acta 1783: 1396–1405.

Lamkanfi M, Declercq W, Kalai M et al. (2002) Alice in caspase land. A phylogenetic analysis of caspases from worm to man. Cell Death & Differentiation 9: 358–361.

Oberst A, Bender C and Green DR (2008) Living with death: the evolution of the mitochondrial pathway of apoptosis in animals. Cell Death & Differentiation 15: 1139–1146.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
da Cunha, Julia Pinheiro Chagas, Galante, Pedro Alexandre F, and de Souza, Sandro José(Dec 2009) Evolution of Caspase‐1 Inhibitors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021743]