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  • Review Article
  • Published:

Making the cut: central roles of intramembrane proteolysis in pathogenic microorganisms

Nature Reviews Microbiology volume 7, pages 411–423 (2009)Cite this article

Key Points

  • Three families of polytopic proteases with membrane-embedded active sites have been discovered: site 2 proteases (S2Ps) are metalloproteases, presenilin-type aspartyl proteases are represented widely by signal peptide peptidases (SPPs) and rhomboid proteins are serine proteases. Intramembrane proteases have received only limited study in microorganisms until recently.

  • Bacteria generally use S2Ps to regulate membrane-tethered transcription factors, and S2Ps are currently known to modulate envelope lipid composition of Mycobacterium tuberculosis, cholera toxin expression, exopolysaccharide synthesis and pheromone-mediated conjugation.

  • The only known role for a bacterial rhomboid is in quorum sensing by Providencia; rhomboid cleaves to activate TatA of the twin-arginine transporter, although most bacteria have the shorter, rhomboid-independent form of TatA. Bacteria lack SPPs.

  • Protozoan pathogens, including the malaria parasite, use rhomboid proteases to cleave adhesins to dismantle the host–parasite junctions at the end of invasion. Other roles in parasite growth are also beginning to emerge, as are roles in phagocytosis and immune evasion by parasitic amoeba.

  • The only known function of any intramembrane protease in a fungal pathogen centres on S2P, which regulates the sterol regulatory element-binding protein (SREBP) pathway to acclimate the pathogen to hypoxia that is encountered during colonization of host tissues.

  • Viruses do not encode intramembrane proteases, but hepatitis C virus uses a cellular SPP enzyme to cleave core protein, which is important for viral assembly. SPP may also participate in the propagation of other viruses.

  • Further work is required to reveal a complete picture of the roles of different intramembrane proteases in pathogens and to evaluate the therapeutic potential of targeting these enzymes.

Abstract

Proteolysis in cellular membranes to liberate effector domains from their transmembrane anchors is a well-studied regulatory mechanism in animal biology and disease. By contrast, the function of intramembrane proteases in unicellular organisms has received little attention. Recent progress has now established that intramembrane proteases execute pivotal roles in a range of pathogens, from regulating Mycobacterium tuberculosis envelope composition, cholera toxin production, bacterial adherence and conjugation, to malaria parasite invasion, fungal virulence, immune evasion by parasitic amoebae and hepatitis C virus assembly. These advances raise the exciting possibility that intramembrane proteases may serve as targets for combating a wide range of infectious diseases. This Review focuses on summarizing the advances, evaluating the limitations and highlighting the promise of this newly emerging field.

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Figure 1: The three families of intramembrane proteases.
Figure 2: S2P circuits and bacterial virulence: variations on a theme.
Figure 3: Dissimilarity in signalling by rhomboid proteases in D. melanogaster and P. stuartii.
Figure 4: Function of rhomboid proteases in two different protozoan parasites.
Figure 5: Fungal S2P mediates adaptation to hypoxia during dissemination.
Figure 6: Cellular SPP processes core protein for hepatitis C virus assembly.

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Acknowledgements

I apologize to those scientists whose work could not be discussed or cited owing to space limitations. I thank R. Baker for expert help with the illustrations. Work in the Urban laboratory is supported by National Institutes of Health grant R01AI066025, a career award from the Burroughs Wellcome Fund and a Packard Foundation Fellowship for Science and Engineering.

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  1. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Room507 PCTB, 725 North Wolfe Street, Baltimore, 21205, Maryland, USA

    Sinisa Urban

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DATABASES

Entrez Genome Project

Bacillus subtilis

Cryptococcus neoformans

Cryptosporidium parvum

Eimeria tenella

Enterococcus faecalis

Entamoeba histolytica

Escherichia coli

Mycobacterium tuberculosis

Plasmodium falciparum

Providencia stuartii

Pseudomonas aeruginosa

Schizosaccharomyces pombe

Toxoplasma gondii

Vibrio cholerae

FURTHER INFORMATION

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Sinisa Urban's laboratory

Glossary

SREBP

A transcription factor that activates the expression of genes required for cholesterol and lipid biosynthesis in animals.

Extracytoplasmic function

Refers to a range of conditions that are commonly detected by the unfolding of outer membrane proteins, which stimulates proteases that liberate E from the membrane to activate the expression of response genes.

Metalloprotease

An enzyme that cleaves peptide bonds using a bound zinc ion to facilitate hydrolysis. The zinc is usually held in place by two conserved histidines and one acidic residue.

Aspartyl protease

A hydrolytic enzyme that uses two aspartate residues to activate water for cleaving peptide bonds.

Serine protease

An enzyme that uses a serine as a nucleophile for cleavage of peptide bonds. The serine is usually activated by a basic residue, and forms a covalent intermediate with the substrate that is released through attack by water.

Anti-sigma factor

A protein that binds and hinders the transcription-activating function of a bacterial sigma factor.

Exopolysaccharide

A linear polymer of modified sugars that is not generally attached to a bacterium and acts as an extracellular matrix.

Nosocomial

An infection acquired in a hospital.

Conjugation

A physical joining of two bacterial cells for the purpose of transferring genetic material.

Quorum sensing

A cell-to-cell signalling mechanism by which bacteria monitor their population size and react to it accordingly.

Pleiotrophic

The state of having multiple, and seemingly unrelated, phenotypes.

Biolog

A commercial, phenotypic testing method conducted using a large number of standardized conditions.

Moving junction

A specialized adhesive point of contact between the parasite and host that appears as an electron-dense structure in electron microscopic analysis, and traverses the surface of the parasite as a tight ring during invasion of the host

Merozoite

The parasitic form specialized for invasion of and replication within erythrocytes.

Band 3

An integral membrane protein responsible for chloride and bicarbonate exchange on erythrocytes.

Microneme

A specialized, apical, tiny, vesicle-like organelle of apicomplexan parasites that houses adhesins and other proteins for secretion during invasion.

Gal–GalNAc lectin

A protein that is specialized for binding sugars, in this case containing galactose and Nacetylgalactosamine.

Azole drug

A class of anti-fungal drug that inhibits the enzyme lanosterol 14a-demethylase, which is required for ergoesterol biosynthesis.

RUP

A form of proteasome degradation that releases intact domains from the membrane into the cytosol.

Lipid droplet

The lipid storage organelle of cells, in which triacylglycerides in the form of a drop are surrounded by a single leaflet of membrane phospholipid.

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Urban, S. Making the cut: central roles of intramembrane proteolysis in pathogenic microorganisms. Nat Rev Microbiol 7, 411–423 (2009). https://doi.org/10.1038/nrmicro2130

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