Isolation of an Isoenzyme of Human Glutaminyl Cyclase: Retention in the Golgi Complex Suggests Involvement in the Protein Maturation Machinery

Cynis, Holger; Rahfeld, Jens‐Ulrich; Stephan, Anett; Kehlen, Astrid; Koch, Birgit; Wermann, Michael; Demuth, Hans‐Ulrich; Schilling, Stephan

doi:10.1016/j.jmb.2008.03.078

Cited by 65 publications

(95 citation statements)

References 48 publications

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“…An extracellular activity of QC might be, therefore, not important for the general maturation process. Thus, isoQC, which is apparently not secreted from the expressing cells in an active form (15) (Fig. 1E), might indeed complement the absence of QC to a certain extent.…”

Section: Discussionmentioning

confidence: 95%

“…Lower QC activity was observed in cerebellum and cortex. Interestingly, the residual enzymatic activity in the knock-out animals appeared to be similar, which suggests a basal expression of the isoenzyme and a more differential expression of QC (15). In order to further investigate the cellular origin of QC activity in the brain, primary cortical neurons were cultured.…”

Section: Generation and Characterization Of Qc Knock-out Animals-mentioning

confidence: 99%

“…Although QC represents a secreted protein, which is apparently involved in hormone maturation in neuroendocrine tissue (14,18), the function of the recently identified isoQC still remains unclear. The retention of the isoenzyme in the Golgi complex might suggest a role in the constitutive protein maturation similar to that of glycosyltransferases (15).…”

mentioning

confidence: 99%

“…Two functional genes, QPCT (QC) and QPCTL (isoQC), encoding glutaminyl cyclases have been described in mammals (15)(16)(17). Although QC represents a secreted protein, which is apparently involved in hormone maturation in neuroendocrine tissue (14,18), the function of the recently identified isoQC still remains unclear.…”

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confidence: 99%

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Glutaminyl Cyclase Knock-out Mice Exhibit Slight Hypothyroidism but No Hypogonadism

Schilling

Kohlmann

Bäuscher

et al. 2011

Journal of Biological Chemistry

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Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate (pGlu) residues at the N terminus of peptides and proteins. Hypothalamic pGlu hormones, such as thyrotropin-releasing hormone and gonadotropin-releasing hormone are essential for regulation of metabolism and fertility in the hypothalamic pituitary thyroid and gonadal axes, respectively. Here, we analyzed the consequences of constitutive genetic QC ablation on endocrine functions and on the behavior of adult mice. Adult homozygous QC knock-out mice are fertile and behave indistinguishably from wild type mice in tests of motor function, cognition, general activity, and ingestion behavior. The QC knock-out results in a dramatic drop of enzyme activity in the brain, especially in hypothalamus and in plasma. Other peripheral organs like liver and spleen still contain QC activity, which is most likely caused by its homolog isoQC. The serum gonadotropin-releasing hormone, TSH, and testosterone concentrations were not changed by QC depletion. The serum thyroxine was decreased by 24% in homozygous QC knock-out animals, suggesting a mild hypothyroidism. QC knock-out mice were indistinguishable from wild type with regard to blood glucose and glucose tolerance, thus differing from reports of thyrotropin-releasing hormone knock-out mice significantly. The results suggest a significant formation of the hypothalamic pGlu hormones by alternative mechanisms, like spontaneous cyclization or conversion by isoQC. The different effects of QC depletion on the hypothalamic pituitary thyroid and gonadal axes might indicate slightly different modes of substrate conversion of both enzymes. The absence of significant abnormalities in QC knock-out mice suggests the presence of a therapeutic window for suppression of QC activity in current drug development.

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Section: Discussionmentioning

confidence: 95%

Section: Generation and Characterization Of Qc Knock-out Animals-mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Glutaminyl Cyclase Knock-out Mice Exhibit Slight Hypothyroidism but No Hypogonadism

Schilling

Kohlmann

Bäuscher

et al. 2011

Journal of Biological Chemistry

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“…2.3.2.5, QC) and its isoenzyme, the iso-glutaminyl cyclase (E.C. 2.3.2.-, isoQC) (Schilling et al 2003, Cynis et al 2008, Cynis et al 2011. Two distinct genes termed QPCT (QC; NM_012413) and QPCTL (isoQC; NM_017659) are coding for the QC activity.…”

Section: Introductionmentioning

confidence: 99%

Role of glutaminyl cyclases in thyroid carcinomas

Kehlen¹,

Haegele²,

Menge³

et al. 2012

Endocrine-Related Cancer

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CCL2 is a chemokine known to recruit monocytes/macrophages to sites of inflammation. CCL2 is also associated with tumor progression in several cancer types. Recently, we showed that the N-terminus of CCL2 is modified to a pyroglutamate (pE)-residue by both glutaminyl cyclases (QC (QPCT)) and its isoenzyme (isoQC (QPCTL)). The pE-residue increases stability against N-terminal degradation by aminopeptidases. Here, we report an upregulation of QPCT expression in tissues of patients with thyroid carcinomas compared with goiter tissues, whereas QPCTL was not regulated. In thyroid carcinoma cell lines, QPCT gene expression correlates with the mRNA levels of its substrate CCL2. Both QPCT and CCL2 are regulated in a NF-kB-dependent pathway shown by stimulation with TNFa and IL1b as well as by inhibition with the IKK2 inhibitor and RNAi of p50. In the culture supernatant of thyroid carcinoma cells, equal amounts of pECCL2 and total CCL2 were detected by two ELISAs discriminating between total CCL2 and pECCL2, concluding that all CCL2 is secreted as pECCL2. Activation of the CCL2/CCR2 pathway by recombinant CCL2 increased tumor cell migration of FTC238 cells in scratch assays as well as thyroid carcinoma cell-derived CCL2-induced migration of monocytic THP1 cells. Suppression of CCL2 signaling by CCR2 antagonist, IKK2 inhibitor, and QPCT RNAi reduced FTC238 cell growth measured by WST8 proliferation assays. Our results reveal new evidence for a novel role of QC in thyroid carcinomas and provide an intriguing rationale for the use of QC inhibitors as a means of blocking pECCL2 formation and preventing thyroid cancer metastasis.

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Common variants in QPCT gene confer risk of schizophrenia in the Han Chinese population

Khan

Chen

Shen

et al. 2015

American J of Med Genetics Pt B

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Schizophrenia (SCZ) is a common and severe mental disorder, its etiology has not been elucidated completely. In one previous genome-wide association study (GWAS) of SCZ in the Caucasian population, the QPCT has been reported as susceptible gene for SCZ. The QPCT gene encodes Glutaminyl cyclase (QC), an enzyme which is involved in the post translational modification by converting N-terminal glutamate of protein to pyroglutamate, which is resistant to protease degradation, more hydrophobic, and prone to aggregation and neurotoxic. To further investigate the role of this gene in the pathogenesis of schizophrenia in the Han Chinese population, we conducted this study in 1,248 (Mean age ± S.D, 36.44 years ± 9.0) SCZ cases, 1,248 (Mean age ± S.D, 30.62 years ± 11.35) healthy control samples for a case control study. We genotyped six SNPs in this study, including one positive SNP of the previous study, using the Sequenom MassARRAY platform. We found that rs2373000 was significantly associated with SCZ before correction [rs2373000: P allele = 0.016, χ(2) = 5.784, OR [95%CI] = 0.861 [0.762-0.972], P genotype = 0.018, χ(2) = 0.069]. After permutation correction for multiple testing, rs2373000 [rs2373000: P Allele corrected = 0.063, P genotype corrected = 0.069] showed marginal association with SCZ. Additionally, one pathogenic haplotype (TGT) containing rs2373000 was also significantly associated with SCZ. Our results are consistent with the findings of previous study and the genetic risk of QPCT gene for SCZ also exists in the Han Chinese population.

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Isolation of an Isoenzyme of Human Glutaminyl Cyclase: Retention in the Golgi Complex Suggests Involvement in the Protein Maturation Machinery

Cited by 65 publications

References 48 publications

Glutaminyl Cyclase Knock-out Mice Exhibit Slight Hypothyroidism but No Hypogonadism

Glutaminyl Cyclase Knock-out Mice Exhibit Slight Hypothyroidism but No Hypogonadism

Role of glutaminyl cyclases in thyroid carcinomas

Common variants in QPCT gene confer risk of schizophrenia in the Han Chinese population

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