The Processing of Human Rhomboid Intramembrane Serine Protease RHBDL2 Is Required for Its Proteolytic Activity
ABSTRACT RHBDL2, a human homolog of the rhomboids, belongs to a unique class of serine intramembrane proteases; little is known about its function and regulation. Here, we show that RHBDL2 is produced as a proenzyme and that the processing of RHBDL2 is required for its cellular protease activity. The processing of RHBDL2 was shown by both Western blot and immunofluorescence analysis. We have demonstrated that a highly conserved Arg residue on loop 1 of RHBDL2 plays a critical role in the activation of the proenzyme. The activation of RHBDL2 is catalyzed by a protease that is sensitive to a class of sulfonamide compounds. Furthermore, endogenous RHBDL2 exists as the processed form and treatment of cells with a sulfonamide inhibitor led to an accumulation of the full length of RHBDL2. Therefore, this study has demonstrated that RHBDL2 activity is regulated by proenzyme activation, revealed a role for the conserved WR residues in loop 1 in RHBDL2 activity, and provided critical insights into the regulation and function of this human rhomboid protease.
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ABSTRACT: The 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 rhomboid-like 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.Molecular and Biochemical Parasitology 12/2011; 182(1-2):27-36. DOI:10.1016/j.molbiopara.2011.11.010 · 2.24 Impact Factor
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ABSTRACT: Rhomboids are ubiquitous intramembrane serine proteases the sequences of which are found in nearly all sequenced genomes, including those of plants. They were molecularly characterized in a number of organisms, and were found to play a role in a variety of biological functions including signaling, development, apoptosis, mitochondrial integrity, parasite invasion and more. Although rhomboid sequences are found in plants, very little is known about their function. Here, we present the current knowledge in the rhomboids field in general, and in plant rhomboids in particular. In addition, we discuss possible physiological roles of different plant rhomboids.Physiologia Plantarum 10/2011; 145(1):41-51. DOI:10.1111/j.1399-3054.2011.01532.x · 3.26 Impact Factor
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ABSTRACT: The Rhomboids represent a relatively recently discovered family of proteins, consisting in a variety of intramembrane serine proteases and their inactive homologues, the iRhoms. Rhomboids typically contain six or seven transmembrane domains (TMD) and have been classified into four subgroups: Secretase A and B, Presenilin-Associated-Rhomboid-Like (PARL) and iRhoms. Although the iRhoms, iRhom1 and iRhom2, have lost their protease activity during evolution, they retain key non-protease functions and have been implicated in the regulation of epidermal growth factor (EGF) signalling. EGF is moreover a substrate of RHBDL2, their active Rhomboid relative. Other substrates of RHBDL2 include members of the EphrinB family and thrombomodulin. RHBDL2 has also previously been demonstrated to be important in wound healing in cutaneous keratinocytes through the cleavage of thrombomodulin. Additional roles for these intriguing proteins seem likely to be revealed in the future. This review focuses on our current understanding of Rhomboids and, in particular, on RHBDL2 and iRhom2 and their roles in cellular processes and human disease.Cell and Tissue Research 12/2012; 351(2). DOI:10.1007/s00441-012-1542-1 · 3.33 Impact Factor