An Entamoeba histolytica rhomboid protease with atypical specificity cleaves a surface lectin involved in phagocytosis and immune evasion

Genes Dev. 2008 Jun 15;22(12):1636-46. doi: 10.1101/gad.1667708.

Abstract

Rhomboid proteases are membrane-embedded enzymes conserved in all kingdoms of life, but their cellular functions across evolution are largely unknown. Prior work has uncovered a role for rhomboid enzymes in host cell invasion by malaria and related intracellular parasites, but this is unlikely to be a widespread function, even in pathogens, since rhomboid proteases are also conserved in unrelated protozoa that maintain an extracellular existence. We examined rhomboid function in Entamoeba histolytica, an extracellular, parasitic ameba that is second only to malaria in medical burden globally. Despite its large genome, E. histolytica encodes only one rhomboid (EhROM1) with residues necessary for protease activity. EhROM1 displayed atypical substrate specificity, being able to cleave Plasmodium adhesins but not the canonical substrate Drosophila Spitz. We searched for substrates encoded in the ameba genome and found EhROM1 was able to cleave a cell surface lectin specifically. In E. histolytica trophozoites, EhROM1 changed localization to vesicles during phagocytosis and to the posterior cap structure during surface receptor shedding for immune evasion, in both cases colocalizing with lectins. Collectively these results implicate rhomboid proteases for the first time in immune evasion and suggest that a common function of rhomboid enzymes in widely divergent protozoan pathogens is to break down adhesion proteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, Protozoan / metabolism
  • Antigens, Surface / metabolism
  • COS Cells
  • Cell Adhesion Molecules / metabolism
  • Chlorocebus aethiops
  • Entamoeba histolytica / enzymology*
  • Entamoeba histolytica / genetics
  • Entamoeba histolytica / physiology
  • Host-Parasite Interactions / immunology
  • Immune Tolerance / physiology*
  • Lectins / metabolism*
  • Lectins / physiology*
  • Molecular Sequence Data
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism*
  • Peptide Hydrolases / physiology
  • Phagocytosis / physiology*
  • Plasmodium / metabolism
  • Protozoan Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • Tissue Distribution
  • Trophozoites / enzymology
  • Trophozoites / metabolism

Substances

  • Antigens, Protozoan
  • Antigens, Surface
  • Cell Adhesion Molecules
  • Lectins
  • Protozoan Proteins
  • Peptide Hydrolases
  • ROM4 protein, Plasmodium falciparum