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  • Review Article
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New lives for old: evolution of pseudoenzyme function illustrated by iRhoms

Nature Reviews Molecular Cell Biology volume 13, pages 489–498 (2012)Cite this article

Subjects

Key Points

  • Genome sequencing has established the prevalence of 'dead enzymes' — homologues of enzymes that have lost their catalytic sites. These enzymes are expressed and conserved, implying that they have a function and are not just genetic debris.

  • Most enzyme families include inactive homologues, and phylogenetic analysis indicates that they can evolve by a variety of strategies: mutagenic loss of catalytic residues is most common, but other types of mutation that, for example, occlude the substrate-binding site are also found.

  • iRhoms, which are inactive homologues of rhomboid proteases, are recently reported examples of dead enzymes that exemplify many of the themes which are common to all inactive homologues.

  • iRhoms are polytopic membrane proteins, resident primarily in the endoplasmic reticulum (ER), that bind to and assist the trafficking of transmembrane domain (TMD) proteins. Drosophila melanogaster iRhom binds epidermal growth factor receptor (EGFR) ligands and promotes their destruction by ER associated degradation. Mouse iRhom2 also binds a single-pass TMD protein, TACE (tumour necrosis factor (TNF)-converting enzyme), but in this case iRhom2 is needed for onward TACE trafficking.

  • iRhoms are novel regulators of membrane protein trafficking, and they are also implicated in several cancers.

  • The rhomboid family has recently been promoted to a superfamily or clan, as it has become clear that more distant proteins, including derlins, are evolutionarily related.

  • Comparison of various dead enzymes reveals common principles of their evolution and function. In particular, they tend to regulate processes in which their enzyme cognates participate, implying that the process of gene duplication followed by loss of enzyme activity provides an excellent foundation from which regulatory proteins evolve.

Abstract

Large-scale sequencing of genomes has revealed that most enzyme families include inactive homologues. These pseudoenzymes are often well conserved, implying a selective pressure to retain them during evolution, and therefore that they have significant function. Mechanistic insights and evolutionary lessons are now emerging from the study of a broad range of such 'dead' enzymes. The recently discovered iRhoms — inactive homologues of rhomboid proteases — have joined derlins and other members of the rhomboid-like clan in regulating the fate of proteins as they pass through the secretory pathway. There is a strong case that dead enzymes, which have been rather overlooked, may be a rich source of biological regulators.

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Figure 1: Evolution of an inactive enzyme homologue from a catalytically active ancestor.
Figure 2: iRhoms and their roles.
Figure 3: Model for evolution of the rhomboid superfamily.
Figure 4: The diversity of mechanisms used by pseudoenzymes.

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Acknowledgements

We thank S. Munro, K. Strisovsky and T. Kloepper for helping to improve the manuscript. This work was supported by the UK Medical Research Council (MRC) programme number U105178780.

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    Colin Adrain & Matthew Freeman

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The MEROPS peptidase database

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Glossary

Pseudogenes

Non-functional gene relatives that have lost their ability to express a functional protein. Can arise through reverse transcription and genome integration, in which case the resulting pseudogene lacks introns and control sequences, or by mutation.

Convergent evolution

The independent acquisition of similar biological characteristics by unrelated phylogenetic lineages.

Divergent evolution

The acquisition of related biological characteristics by diversification of a common ancestor.

Endoplasmic reticulum-associated degradation

(ERAD). A cellular quality control mechanism in which ER proteins undergo retrotranslocation back to the cytoplasm to be targeted for destruction by the proteasome.

Unfolded protein response

(UPR). A response to the stress of potentially damaging accumulation of unfolded proteins in the endoplasmic reticulum of eukaryotic cells. During UPR, protein translation is inhibited, and molecular chaperones that can aid protein refolding are induced.

Last universal common ancestor

(LUCA). The last ancient organism from which all current organisms descended.

Horizontal gene transfer

(HGT). An evolutionary mechanism by which genes are directly transferred between species independently of reproduction. Contrasts with vertical gene transfer from parent to offspring. HGT is thought to be a biologically significant process among single-celled organisms.

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Adrain, C., Freeman, M. New lives for old: evolution of pseudoenzyme function illustrated by iRhoms. Nat Rev Mol Cell Biol 13, 489–498 (2012). https://doi.org/10.1038/nrm3392

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