The cytokine tumor necrosis factor (TNF) is the primary trigger of inflammation. Like many extracellular signaling proteins, TNF is synthesized as a transmembrane protein; the active signal is its ectodomain, which is shed from cells after cleavage by an ADAM family metalloprotease, TACE/ADAM17. We report that iRhom2/RHBDF2, a proteolytically inactive member of the rhomboid family, is required for TNF release in mice. iRhom2 binds TACE and promotes exit from the endoplasmic reticulum. The failure of TACE ER exit in the absence of iRhom2 prevents furin-mediated maturation and its trafficking to the cell surface, the site of TNF cleavage. Given the role of TNF in autoimmune and inflammatory diseases, iRhom2 may represent an attractive therapeutic target.Proteolytic release of the extracellular domain of transmembrane proteins is an important mechanism for generating signals that regulate major aspects of animal development, physiology, immunity and pathology (1, 2). An important example of regulated ectodomain shedding is the cytokine TNF, the primary trigger of inflammatory responses. TNF is associated with many human diseases including rheumatoid arthritis, Crohn's disease, atherosclerosis, psoriasis, sepsis, diabetes, and obesity. Its blockade is licensed as a therapy for a number of conditions, and is being assessed for others (3). Soluble, active TNF is shed from the plasma membrane by the ADAM family metalloprotease TACE (TNFα converting enzyme; also known as ADAM17) (4). Despite the medical importance of TNF and other transmembrane signaling proteins, the regulation of ectodomain shedding remains poorly understood. Both the transmembrane forms of the signaling proteins themselves, and the shedding proteases, are subject to control by posttranslational modification, interaction with specific partners, and regulated intracellular trafficking and compartmentalization (5-9). The relative physiological importance, however, of these different modes of regulation is unclear.We have investigated the regulation of ectodomain shedding by genetic and cellular approaches, both in Drosophila and mammalian cells. This has led to the recent discovery of a new class of polytopic endoplasmic reticulum (ER) proteins, the iRhoms, which are noncatalytic relatives of rhomboid intramembrane proteases (Fig. 1A) (10). Drosophila iRhom regulates epidermal growth factor (EGF) receptor signaling by interacting with EGF family ligands in the ER, shunting them into the ER-associated degradation (ERAD) pathway (11). iRhoms are conserved in all metazoans, and in cell culture assays their mammalian Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts counterparts, iRhom1 and iRhom2, can also promote ERAD of EGF. In mammals, however, their physiological role is unknown. We therefore generated a null mutation in the gene that encodes iRhom2/RHBDF2 in mice (Fig. S1A). iRhom2 −/− mice appeared normal: they were viable and fertile, with no morphological defects. Unlike iRhom1, which is widely expressed, iRhom2 is...
The amyloid peptide is the main constituent of the amyloid plaques in brain of Alzheimer's disease patients. This peptide is generated from the amyloid precursor protein by two consecutive cleavages. Cleavage at the N terminus is performed by the recently discovered -secretase (Bace). This aspartyl protease contains a propeptide that has to be removed to obtain mature Bace. Furin and other members of the furin family of prohormone convertases are involved in this process. Surprisingly, -secretase activity, neither at the classical Asp 1 position nor at the Glu 11 position of amyloid precursor protein, seems to be controlled by this maturation step. Furthermore, we show that Glu 11 cleavage is a function of the expression level of Bace, that it depends on the membrane anchorage of Bace, and that Asp 1 cleavage can be followed by Glu 11 cleavage. Our data suggest that pro-Bace could be active as a -secretase in the early biosynthetic compartments of the cell and could be involved in the generation of the intracellular pool of the amyloid peptide. We conclude that modulation of the conversion of pro-Bace to mature Bace is not a relevant drug target to treat Alzheimer's disease.
The proprotein convertases (PCs) are a seven-member family of endoproteases that activate proproteins by cleavage at basic motifs. Expression patterns for individual PCs vary widely, and all cells express several members. The list of substrates activated by PCs has grown to include neuropeptides, peptide hormones, growth and differentiation factors, receptors, enzymes, adhesion molecules, blood coagulation factors, plasma proteins, viral coat proteins, and bacterial toxins. It has become clear that the PC family plays a crucial role in a variety of physiological processes and is involved in the pathology of diseases such as cancer, viral infection, and Alzheimer's disease. Recent studies using PC inhibitors have demonstrated their potential as therapeutic targets. Despite the avalanche of in vitro data, the physiological role of individual PCs has remained largely elusive. Recently, however, knockout mouse models have been developed for furin, PC1, PC2, PC4, PC6B, LPC, and PACE4, and human patients with PC1 deficiency have been identified. The phenotypes range from undetectable to early embryonic lethality. The major lesson learned from these studies is that specific PC-substrate pairs do exist, but that there is substantial redundancy for the majority of substrates. To some extent, redundancy may be cell type and even species dependent.
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