It has been reported that this expression of this small non-coding RNA changes during postnatal development [85,86], raising the possibility that RPN2 expression is cell-context-dependent and regulated dynamically during development and oncogenesis. TUSC3 has been identified as a candidate tumor suppressor [53]. Importantly, a recently developed inhibitor of OST has revealed this enzyme as a potential target for the treatment of incurable drug-resistant tumors. This review summarizes our current knowledge regarding the functions of OST in the light of health and tumor progression, and discusses perspectives around the clinical relevance of inhibiting OST as a tumor treatment. gene is usually duplicated and the gene products (STT3A and STT3B) are expressed to mediate N-glycosylation in a mutually complementary manner (observe below) (Physique 1) [23]. 3. OST and Its Action Mammalian cells express two unique OST complexes that contain STT3A or STT3B as the catalytic subunits and several accessory proteins (Physique 2 and Table 1; STT3A-OST and STT3B-OST) [24,25,26,27]. These accessory proteins include six common subunits (RPN1, RPN2, OST48/DDOST, OST4, TMEM258 and DAD1), STT3A-OST-specific subunits (DC2/OSTC and KCP2) [28] and STT3B-OST-specific subunits (TUSC3 and MAGT1) [17,29]. The two OST complexes are known to have distinct, but partially overlapping specificity to DLO glycans and acceptor sites [23,24,30,31,32,33]. Regarding DLO glycans, it has been reported that in vitro, STT3A-OST shows a rigid specificity to the fully put together DLO, whereas STT3B-OST can also accept DLOs that are completely devoid of glucose residues [24]. The glucose residues of DLO are required for the efficient binding of STT3A-OST, but not STT3B-OST, to acceptor peptides, indicating that the glycan moiety of the fully put together DLO promotes N-glycosylation by STT3A-OST [24]. STT3 orthologs contain an evolutionarily conserved external loop T-5224 5 (EL5), which binds to both donor and acceptor substrates via its N-terminal and C-terminal regions, respectively [34]. It has been proposed that this EL5 loop of PglB, a bacterial ortholog of STT3, controls the accessibility of the glycan moiety of lipid-linked oligosaccharides to the active site of PglB. Although the precise role of the EL5 loop of mammalian STT3 proteins in catalysis remains unknown, it is attractive to speculate that this microenvironment surrounding the EL5 loop is usually distinctly different between STT3A-OST and STT3B-OST, which could limit the full activation of STT3A-OST by incompletely put together DLOs. In support of this hypothesis, DC2, a STT3A-OST-specific subunit, is usually in contact with the second transmembrane domain name of STT3A, which is located close to the EL5 loop [35]. Open in a separate windows T-5224 Physique 2 Subunit composition of STT3A-OST and STT3B-OST. STT3A-OST (upper side) and STT3B-OST (lower side) contain six shared subunits (RPN1, RPN2, DAD1, OST48, OST4, and TMEM258; shown in orange) and specific subunits (DC2/OSTC and KCP2 for STT3A-OST; shown in dark blue, and TUSC3 and MAGT1 for STT3B-OST; shown in cyan). The cytosolic domain name of RPN1 in complex with STT3A-OST makes contact with the 60S subunit of membrane-bound ribosomes [35]. In contrast, DC2/OSTC mediates conversation between STT3A-OST and Sec61 protein-conducting channel [35], allowing co-translational N-glycosylation. STT3B-OST contains either one of TUSC3 or MAGT1, which has an oxidoreductase activity and facilitates N-glycosylation of Cys proximal sites [33]. N-glycosylation inhibitor 1 (NGI-1) inhibits STT3B-OST more efficiently than STT3A-OST (represented by solid and thin T bars) [43]. Table 1 Subunit compositions and functions of oligosaccharyltransferase (OST). or gene causes type I congenital disorders of glycosylation (CDGs) with similar symptoms [42], highlighting the need of both N-glycosylation activities for health. The N-glycosylation status of serum transferrin has been used to identify type I CDGs. Transferrin contains two N-glycosylation sites, which are altered by STT3A [32], and is therefore greatly hypoglycosylated in STT3A-CDG [42]. Consistent with this substrate specificity of OST, the N-glycosylation of transferrin is usually affected only moderately in STT3B-CDG [42]. The identification of other serum glycoproteins that have STT3B-dependent sites will be required for the routine identification of patients with STT3B-CDG. 4. Functions of Accessory OST Subunits in N-Glycosylation and Health Although accessory subunits of OST are required T-5224 for structural integrity and the maximal activity of OST, their biological functions are not fully comprehended. Here we summarize important proposed functions of the accessory subunits of OST in N-glycosylation and complex formation (Table 1). Genetic disorders caused by OST deficiency are also discussed. 4.1. Shared Subunits GNGT1 RPN1 and RPN2 (Ost1 and Swp1 in yeast, respectively) are OST subunits shared by both STT3A-OST and STT3B-OST. These proteins were originally identified as potential receptors of membrane-bound ribosomes [44], referred to as ribophorins. A cryo-electron microscopy (EM) model of STT3A-OST complexed with the membrane-bound ribosomes and Sec61 protein-conducting channel revealed.