© Borgis - Postępy Nauk Medycznych 11/2011, s. 917-923
*Marlena Godlewska1, Andrzej Gardas1, Monika Góra2
Biosynthesis, post-translational modifications, maturation, and physiological function of human thyroid peroxidase**
Biosynteza, modyfikacje postranslacyjne, dojrzewanie i fizjologiczna funkcja ludzkiej peroksydazy tarczycowej
1Department of Biochemistry and Molecular Biology, Medical Centre of Postgraduate Education, Warsaw
Head of Department: prof. dr hab. Barbara Czarnocka
2Department of Genetics, Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw
Head of Department: prof. dr hab. Teresa Żołądek
Peroksydaza tarczycowa (TPO) jest jednocześnie głównym autoantygenem w autoimmunologicznych chorobach tarczycy i kluczowym enzymem, wraz z białkami DUOX, odpowiedzialnym za syntezę hormonów tarczycy. Jeszcze na poziomie retikulum endoplazmatycznego nowo zsyntetyzowana TPO przechodzi proces N-glikozylacji i włączania hemu oraz przejściowo oddziałuje z białkami opiekuńczymi (chaperonami). Następnie podczas transportu przez aparat Golgiego do cząsteczki TPO dołączane są O-glikany, natomiast oligosacharydy połączone z białkiem wiązaniem N-glikozydowym poddawane są dalszym modyfikacjom. Po opuszczeniu aparatu Golgiego, ale przed dotarciem na powierzchnię komórki, z peroksydazy zostaje usunięty propeptyd. TPO tworzy dimery, jednak mechanizm tego procesu jest nadal nieznany. Tylko część zsyntetyzowanego białka dociera do błony komórkowej, natomiast cząsteczki z częściowym lub całkowitym zaburzeniem struktury przestrzennej są degradowane w retikulum endoplazmatycznym przez odpowiednio proteasom lub proteazę podobną do plazminogenu.
Apart from being the major target autoantigen in autoimmune thyroid disease, thyroid peroxidase (TPO) is the key enzyme, together with DUOX proteins, responsible for the thyroid hormone generation. Newly synthesized TPO is processed in the endoplasmic reticulum, undergoing N-glycosylation, heme fixation, and transient interaction with molecular chaperones. Then, while transporting through the Golgi apparatus, O-glycans are attached to the TPO molecule, whereas N-linked oligosaccharides undergo further modifications. After exiting the Golgi, but before it reaches the cell surface, the propeptide is removed. TPO forms dimers, however, the mechanism of this process is still unknown. Only part of the synthesized TPO reaches the cell membrane, whereas partially or totally misfolded forms of TPO are degraded in the endoplasmic reticulum by the proteasome or a plasminogen-like protease, respectively.
Since 1985 we have known that human thyroid peroxidase (TPO), previously known as the thyroid microsomal antigen, is a target for the autoimmune response in autoimmune thyroid diseases (1). The majority of patients’ autoantibodies to thyroid peroxidase are directed to two discontinuous determinants on the protein surface. Several approaches have been taken by our and other laboratories to localize the autoantibody binding regions on TPO. These studies provided a greater insight into the nature of the autoimmune response to the thyroid. In a few recent reviews the current knowledge on TPO as an autoantigen was summarized (2-5). Here, we focus on the biochemical aspects of thyroid peroxidase, especially on its maturation process, trafficking and participation in thyroid hormone biosynthesis.
Protein structure and expression
The human TPO gene, that was cloned in 1987 (6-8), is located on chromosome 2 (region pter-p12) and it is composed of 17 exons and 16 introns (9). The TPO expression is controlled by thyroid-specific factors, namely TTF-1, TTF-2, and Pax-8 (reviewed in Ref. 10-12). Till now several isoforms of TPO cDNA were identified, cloned and characterized (reviewed in Ref. 2, 10).
TPO belongs to the animal peroxidase protein family together with myeloperoxidase (MPO), lactoperoxidase (LPO), eosinophil peroxidase (EPO) (reviewed in Ref. 13, 14). TPO, a 933 amino-acid residues polypeptide, contains ectodomain, single membrane-spanning region and short intracellular tail (15). The dominant part of the protein, called ectodomain, consists of three distinct domains, namely MPO-like domain with high homology to myeloperoxidase (residues 142-738), CCP-like domain similar to complement control protein (residues 739-795), and EGF-like domain that is homologous to the epidermal growth factor (residues 796-841) (15). A three-dimensional computer model of TPO ectodomain was constructed in our laboratory, however, the localization of all TPO domains relatively to each other is still unknown (15). Till now the attempts to solve the TPO structure by X-ray crystallography ended in failure (16, 17). On the contrary, the crystal structure of other two members of the animal peroxidase family, namely MPO (18, 19) and LPO (20), has been already determined.
The TPO molecule undergoes a few modifications while biosynthesis, that are glycosylation, heme incorporation, propeptide removal, and dimer formation (fig. 1). TPO ectodomain contains five predicted N-glycosylation sites in the amino-acid sequence (Asn129, Asn307, Asn342, Asn478, and Asn569) (6-8). However, glycosylation at position 478 probably does not occur because the X residue of the Asn-X-Thr consensus sequence is proline (21). It is well documented that N-linked oligosaccharides are added to the nascent protein in the endoplasmic reticulum (ER) (reviewed in Ref. 22). At this stage, the glycoprotein contains high mannose oligosaccharides that are sensitive to endoglycosidase H (Endo H) digestion. During the passage through the Golgi apparatus, glycoprotein undergoes a final process of N-glycosylation resulting in the transformation of Endo H-sensitive high mannose oligosaccharides to Endo H–resistant complex oligosaccharides. Thus, susceptibility to Endo H digestion is used to distinguish between high-mannose and complex oligosaccharides and help in differentiation whether the protein is before or after transit through the Golgi apparatus (reviewed in Ref. 22).
Fig. 1. TPO processing scheme. High mannose oligosaccharide side chains and heme group are incorporated to the TPO translation product in the endoplasmic reticulum. Signal peptide cleavage occurs also in this compartment (like in MPO) (reviewed in Ref. 47) or later during TPO transport to the cell surface (no data available). Some O-glycan side chains (not shown in this scheme), as well as complex N-glycan chains, are added to the TPO polypeptide in the Golgi apparatus. The propeptide is removed after its transit through the Golgi apparatus but before it reaches the plasma membrane. Mature TPO forms dimers (not shown in this scheme), however, the localization of dimerisation process in the cell is still unknown.
N-glycans content in human TPO was debated. The hypothesis, that TPO acquires complex oligosaccharides during maturation, was confirmed in research on TPO purified from human thyroid (23, 24), full-length TPO produced in insect (25) and CHO cells (26, 27), TPO ectodomain expressed in insect (24, 28) and CHO cells (28). Deglycosylation analysis of intracellular and cell surface fractions of TPO expressed in CHO cells showed that, inside the cell, this protein contains only high mannose-type structures, whereas TPO at plasma membrane bears complex-type structures (26). However, there are some reports suggesting that TPO contains only high mannose structures regardless of whether the protein is expressed in CHO cells (29) or is purified from thyroid gland (30). Additionally, other studies showed that TPO exiting ER does not necessarily acquire endoglycosidase H resistance (31). Human TPO produced in MDCK (Madin-Darby Canine Kidney) cells was Endo H-sensitive inside the cell and at the cell membrane. The same protein transfected to PC Cl3 (rat thyrocytes) was predominantly sensitive (about 75%) to Endo H digestion (being integrated to the plasma membrane) indicating the lack of conversion to complex carbohydrates upon passage through the Golgi complex (31). Nevertheless, in the same study it was observed that TPO ectodomain secreted to the medium by CHO cells was resistant to the endoglycosidase H digestion. The phenomenon of not acquiring Endo H resistance upon trafficking through the Golgi was earlier observed and it may be explained by the inaccessibility of high mannose oligosaccharides in the tertiary and quaternary structure (32). However, it needs explanation why in some studies the modification of these inaccessible high mannose N-glycans is possible.
N-linked oligosaccharide moieties serve various functions, e.g., stabilize the proteins against denaturation and proteolysis, improve solubility, modulate immune response, regulate protein turnover, stabilize the structure of proteins, and promote their adequate sorting and quality control (reviewed in Ref. 22, 33). The role of these units in TPO was examined. After Endo H treatment, the specific activity of TPO purified from human thyroid, measured by guaiacol and iodide oxidation assays, was reduced about 4 times in comparison to non-deglycosylated protein (30). The authors confirmed that the aggregated state of the molecule, that could be induced by the glycans removal, was not responsible for this decrease (30). They assigned this reduction to the modification of the molecule’s conformation at the enzymatic site (30). Kiso et al. (23) also demonstrated that enzymatic activity of native TPO treated with endoglycosidase H was significantly lower, when measured with guaiacol assay, but no effect was observed in the iodide oxidation assay. In further studies, the inhibition of N-glycosylation using tunicamycin (Tu) reduced by half enzymatic activity of human TPO at the cell surface in CHO cells (26). When the cells were treated with deoxymannojirimycin (dMM) which leads only to high mannose-type structures formation, the activity was not (or only slightly) reduced (26). The cell surface expression of newly synthesized TPO, after treatment with Tu, was almost totally blocked (by 95%) what may explain the decrease in enzymatic activity. All in all, it seems that N-glycans play an essential role in the intracellular trafficking and enzymatic activity of TPO. Additionally, the reactivity of unglycosylated TPO with anti-TPO antibodies, namely human autoimmune antibodies (23, 29, 30), mouse monoclonal antibodies (26, 30), and rabbit polyclonal antibodies (30), was determined. The conclusion was that the tertiary structure of epitopes recognized by anti-TPO antibodies is not markedly changed (23, 29, 30), however, the opposite observations were made by Fayadat et al. (26). Finally, as will be discussed later, N-linked oligosaccharides mediate the interaction between TPO and molecular chaperones (calnexin, calreticulin, and BiP) (34, 35).
The incorporation of O-glycans to human TPO was also analyzed. TPO purified from human thyroid (23), full-length human TPO expressed both in insect (25) and CHO cells (26) undergoes O-glycosylation. Opposite conclusions were drawn from the experiments conducted on full-length human TPO (29) and human TPO ectodomain (28), both expressed in CHO cells. In more detailed study, after separation of intracellular and cell-surface TPO, it was shown that only TPO localized in the latter fraction bears O-glycans (26). This finding was in agreement with the fact that O-glycosylation process occurs in the Golgi apparatus (reviewed in Ref. 33). O-glycans removal from native TPO, isolated from human thyroid gland, probably has no impact on enzymatic activity and interaction with autoantibodies (23). The treatment of the TPO-expressing CHO cells with phenyl-α-GalNAc, a specific inhibitor of O-glycosylation, only slightly altered TPO traffic to the cell surface and activity of this protein, nevertheless, the role of O-linked carbohydrates in the protection of TPO against proteolysis cannot be excluded (26).
The nature of the heme prosthetic group of TPO is still unclear. It was postulated that hog TPO contains other heme group than ferriprotoporphirin IX (36, 37). In other works, it was suggested that ferriprotoporphirin IX or other closely related porphyrin might be incorporated to the molecule of bovine (38) and hog TPO (39, 40). The probable localization in the TPO structure of proximal histidine (linked to the iron centre of the heme) and distal histidine (situated close to the peroxide binding pocket) was firstly proposed by Kimura and Ikeda-Saito (41). They indicated His407 or His414 as the candidates for the proximal and His494 or His586 as the probable distal ligand. More recently, His494 (42, 43) and His239 (43) were pointed out as possible proximal and distal histidine residues, respectively. It is hypothesized that Glu399 and Asn238 are bound covalently to the heme prosthetic group through ester linkage (43, reviewed in Ref. 44).
The group of JL Franc (45) investigated the role of the heme moiety insertion in the exit of TPO from the endoplasmic reticulum. The treatment of TPO expressing CHO cells with succinyl acetone (SA), an inhibitor of heme biosynthesis, resulted in significant reduction in peroxidase activity at the cell surface and cell surface expression of TPO. On the contrary, supplementation of the culture medium with precursors of heme biosynthesis improved the TPO delivery to the cell membrane and TPO activity in this compartment. Thus, it seems that heme incorporation plays an essential role in the intracellular trafficking of TPO. In the same study, the role of H2O2 in heme binding to the TPO molecule was investigated (45). It was demonstrated, both in TPO-CHO cells and in porcine thyroid primoculture, that heme is autocatalytically modified in the presence of H2O2 and subsequently covalently linked to the TPO protein. This process starts inside the cell, where H2O2 is probably generated by electron transfer reactions (in CHO and thyroid cells), and it is continued at the cell surface, where H2O2 is produced by DUOX1 and DUOX2 (in thyroid cells). Unlike in thyrocytes, the surface H2O2-generating system is not present in TPO-CHO cells, therefore, H2O2 supplementation significantly improves the autocatalytic covalent attachment of heme in this cell line (45).
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