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Intriguing Parasites and Intramembrane Proteases Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE Intriguing parasites and intramembrane proteases Robert B. Rawson1 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Rhomboid intramembrane proteases occur throughout The parasitic lifestyle the kingdoms of life. In this issue of Genes & Develop- Parasitism poses common challenges to the diverse or- ment, Baxt and colleagues (pp. 1636–1646) report that ganisms that practice it. Parasites must first locate and the single proteolytic rhomboid (EhROM1) from Ent- enter a host. Next, in many cases, host tissues or cells amoeba histolytica cleaves cell surface galactose-bind- must be invaded, requiring some means of attachment ing or N-acetylgalactosamine-binding (Gal/Gal-NAc) and introgression. The successful parasite usually estab- lectins. EhROM1 and lectins colocalize during phagocy- lishes a long-term infection, and this potentially affords tosis and receptor capping. EhROM1 is found at the base the host ample time to mount a vigorous immune re- of the cap rather than in the cap proper, suggesting a role sponse to the invader. In order to survive and reproduce in receptor shedding and implying that EhROM1 is cru- while “dining at another’s table,” the parasite must cial for amoebal infection. somehow manage to evade host immune defenses that may act at several stages of the infection cycle. Broadly, Parasitic protists are fascinating organisms in their own extracellular parasites are subject to the humoral re- right, with their typically complex life cycles, distinctive sponse, while intracellular stages are the target of cellu- physiologies, and uncertain relationships. They are of lar immunity. immense practical interest as well; parasitic infections account for an enormous proportion of the disease bur- den on the human population worldwide. The debilitat- Invasion and evasion ing and often lethal parasitic diseases remain among the Strategies for evading the host immune response are as most intractable infections and result in between 1.5 and complex and varied as the parasites that use them, and 3 million deaths annually. The enormous costs resulting most parasites use several different strategies in the from lost productivity and caring for the millions who course of infection. Parasites may engage various re- suffer from parasitic disease represent significant hurdles sponses to the host immune system (Zambrano-Villa et to economic development throughout the world, and al. 2002). Some parasites synthesize proteases that spe- these burdens tend to be the highest where the resources cifically target components of the host immune machin- to bear them are the least. Advances in our understand- ery for destruction. Others send out molecules that ing of parasites, such as how they initiate and maintain mimic chemokines and suppress the immune response infections, therefore, have significant potential to im- (Goodridge and Harnett 2005). In any event, modulating prove human health and well-being worldwide. the host’s immune response is a delicate matter. If a Among parasitic diseases, amoebiasis ranks second parasite disables the response sufficiently, competitors only to malaria in global morbidity, affecting vast num- may then flourish in the immunocompromised host. bers of people worldwide and killing some 100,000 an- Once the host succumbs, the parasite loses its meal nually (World Health Organization 1997). The causative ticket. Thus, strategies for dealing with the immune re- agent of human amoebiasis, Entamoeba histolytica, sponse are varied and subtle. faces many of the same challenges faced by other para- Many parasites have intricate life cycles involving sites when establishing infection. Baxt et al. (2008) detail multiple hosts and multiple developmental stages, each the role of the single rhomboid intramembrane protease with its own characteristic array of antigenic proteins, from E. histolytica in crucial parasite processes: phago- even within a single host. The malarial parasite Plasmo- cytosis and immune evasion. dium falciparum, for example, shuttles between intra- and extracellular modes, moving from mosquito saliva to the bloodstream to hepatocytes and on to erythro- [Keywords: Serine protease; presenilin; site-2 protease; erythrophagocy- cytes. At each stage, different antigens are elaborated tosis; immune evasion; pathogenesis] (Kilejian 1980), and even within a single stage the dom- 1Correspondence. E-MAIL [email protected]; FAX (214) 648-8804. inant antigens can change, enabling the parasite to Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1686808. “hide” functionally from the host (Plebanski et al. GENES & DEVELOPMENT 22:1561–1566 © 2008 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/08; www.genesdev.org 1561 Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Rawson 1997)—by the time an effective response to one antigen predisposition to early-onset Alzheimer’s disease in cer- is mounted, the parasite is presenting the immune sys- tain families. They are aspartyl proteases comprised of tem with a new one. If, after switching antigens, the multiple membrane-embedded helices. parasite still faces immune challenge, it may simply Amyloid ␤ is released in two sequential steps: First, ␤ shed the targeted antigens (Howell et al. 2003), much as secretase cleaves APP within its luminal domain, near a lizard may lose its tail to escape a menacing cat. E. the surface of the membrane, and then ␥ secretase histolytica uses a unique variation of this strategy, called cleaves it within its membrane-spanning helix (Selkoe capping (Fig. 1). The effectiveness of these various eva- 1996). In addition to APP, presenilins are required for the sive strategies, alone or in combination, may account, in cleavage of other proteins such as Notch (Baumeister et part, for the limited success of antiparasite vaccination al. 1997; De Strooper et al. 1999). strategies. Site-2 protease (S2P) Intramembrane proteolysis and parasitic infection Excessively high levels of cholesterol in the blood- Intramembrane proteolysis is an evolutionarily ancient stream, hypercholesterolemia, leads to atherosclerosis, signal transduction mechanism occurring widely in or- vascular disease, and death. Efforts to understand the ganisms ranging from prokaryotes to people (Brown et al. global regulation of cholesterol metabolism in cells lead 2000). It was first uncovered a dozen years ago during to the identification of the sterol regulatory element- efforts to understand diseases that are far more common binding protein (SREBP) transcription factors (Brown and in the aging populations of industrialized societies than Goldstein 1999). SREBPs are made as precursors that re- are parasitic diseases: atherosclerosis and Alzheimer’s side initially in the ER membrane, owing to their two disease. membrane-spanning helices. The transcriptionally ac- tive N-terminal domain is released from the membrane by sequential cleavage of the precursor by two distinct ␥ Secretase proteases. The site-1 protease, a typical serine protease of the secretory pathway, anchored to the membrane by a Among the hallmarks of Alzheimer’s disease are the so- single membrane-spanning helix, cleaves SREBPs in the called amyloid plaques that are associated with neuro- short luminal sequence that separates its two mem- degeneration. These plaques are formed largely of pro- brane-spanning helices. The second cleavage occurs near tein fragments from the amyloid precursor protein (APP). the membrane surface, within the first membrane-span- Release of these fragments, called amyloid ␤ peptide, re- ning helix (Sakai et al. 1996; Duncan et al. 1998). quires two separate cleavages by two distinct enzymes: ␤ Cloning and sequencing the S2P cDNA revealed S2P secretase and ␥ secretase. to be a large, unusually hydrophobic metalloprotease un- ␤ Secretase (or BACE) is an aspartyl protease . Its active related to any previously described protein. Topological site lies within a large domain that is disposed to the studies suggested that the active site was at or within the lumen of the secretory pathway. BACE is anchored to plane of the bilayer (Zelenski et al. 1999). This inference the membrane by a single membrane-spanning helix. ␥ is supported by recent crystal structure analysis of a bac- Secretase is a large complex composed of multiple poly- terial S2P homolog (Feng et al. 2007). peptide chains (Kimberly et al. 2003) including preseni- S2P was the first intramembrane-cleaving protease (or lin, which harbors the active site. The presenilins were I-CliP) (Wolfe et al. 1999a) to be identified (Rawson et al. originally identified by their genetic association with 1997). Subsequently, the presenilins were shown to be the ␥ secretases (Wolfe et al. 1999b). These observations lead to the recognition of regulated intramembrane pro- teolysis as a widespread and ancient signal-transduction mechanism (Brown et al. 2000). Signal peptide peptidase (SPP) Studies of the fate of cleaved signal peptides lead to the identification of another family of aspartyl intramem- brane proteases, the signal peptide peptidases (Weihofen et al. 2002). Outside of their conserved active sites, SPP and presenilin show no significant sequence similarity Figure 1. Surface receptor capping in Entamoeba histolytica. and SPP cleaves type II (N terminus cytoplasmic)
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