New insights into parasite rhomboid proteases

Abstract

a b s t r a c tThe rhomboid-like proteins constitute a large family of intramembrane serine proteases that are present in all branches of life. First studied in Drosophila, these enzymes catalyse the release of the active forms of proteins from the membrane and hence trigger signalling events. In protozoan parasites, a limited number of rhomboid-like proteases have been investigated and some of them are associated to pathogenesis. In Apicomplexans, rhomboid-like protease activity is involved in shedding adhesins from the surface of the zoites during motility and host cell entry. Recently, a Toxoplasma gondii rhomboid was also implicated in an intracellular signalling mechanism leading to parasite proliferation. In Entamoeba histolytica, the capacity to adhere to host cells and to phagocytose cells is potentiated by a rhomboid-like protease. Survey of a small number of protozoan parasite genomes has uncovered species-specific rhomboidlike protease genes, many of which are predicted to encode inactive enzymes. Functional investigation of the rhomboid-like proteases in other protozoan parasites will likely uncover novel and unexpected implications for this family of proteases.

The role of proteases in regulating Eph/ephrin signaling

“…Three major groups of Rhomboids have been described: Rhomboid-like proteases (active rhomboids), iRhoms (inactive rhomboids) and other inactive rhomboid-like proteins. 138 Unlike most of the other serine proteases, Rhomboids use a catalytic dyad consisting of serine and histidine. 139 Drosophila Rhomboid-1 cleaves the EGF-like growth factor Spitz, 140 and similarly, human EGF is a substrate of the mammalian rhomboid RHBDL2, cleaving just outside its transmembrane domain, thereby facilitating the activation of the EGF receptor.…”

Bioinformatics perspective on rhomboid intramembrane protease evolution and function

“…Instead, an alternate scenario of rhomboid protease origination in bacteria and acquisition by archaea and eukaryotes through multiple ancient horizontal gene transfers (HGT) was proposed [11]. Subsequent to this work, evolutionary analyses of rhomboid proteases has concentrated on eukaryotic members [14], with some independent considerations of gene expansions in apicomplexan parasites [12] and in plants [15]. While only one study has focused on bacteria, limiting analysis to mycobacterial species [13].…”

“…Rhomboid proteases have also expanded in apicomplexan parasites and in land plants, and their phylogenetics have been considered independently by several groups [12, 14–16]. Apicomplexan parasites contain multiple diverse copies of rhomboid proteases, including a single widely distributed PARL-type protease ( ROM6 ) that localizes to the mitochondria and has duplicated in Plasmodium ( ROM9 ) [12, 14].…”

“…Apicomplexan parasites contain multiple diverse copies of rhomboid proteases, including a single widely distributed PARL-type protease ( ROM6 ) that localizes to the mitochondria and has duplicated in Plasmodium ( ROM9 ) [12, 14]. The remaining rhomboid protease members segregate with ROM4/ROM5 forming a close group that separates from the less widely distributed ROM7 and ROM1-3 .…”

“…The remaining rhomboid protease members segregate with ROM4/ROM5 forming a close group that separates from the less widely distributed ROM7 and ROM1-3 . These non-PARL rhomboid proteases were described as being unique to apicomplexans, possibly functioning in parasite specific processes [12]. However, the question remains as to whether these families are indeed distinct from other eukaryotic groups, originating independently in parasites, or they have diverged so much from the eukaryotic RHOs that the family groupings are not evident.…”