Functions of glutaminyl cyclase and its isoform in diseases

Abstract

Glutaminyl cyclase (QC; isoform: isoQC) is a zinc-dependent enzyme that catalyzes the intramolecular cyclization of N-terminal glutamine and glutamic acid residues into a pyroglutamate residue (pGlu). This conversion is a type of posttranslational modification called pyroglutamylation. The expression of QC/isoQC is regulated by epigenetics, cell homeostasis, and its substrates. Pyroglutamylation is an important maturation process during the synthesis and secretion of hormones, functioning in different diseases, such as Alzheimer’s disease, tumors, and other kinds of chronic diseases mediated by inflammation. IsoQC has been identified as a key regulator of the CD47-SIRPα checkpoint and is critical for the pyroglutamylation of CD47 at its SIRPα binding site, thus helping cancer cells evade immune surveillance. Inhibition of isoQC blocks the interaction between CD47 and SIRPα, leading to constrained tumor growth, indicating that isoQC is a novel target for immunotherapy. Targeting isoQC overcomes the side effects of targeting CD47 because isoQC is Golgi resident and is not expressed on erythrocytes. Small molecules and antibodies have been developed to target isoQC, and some of them have been tested in preclinical or clinical studies. Here, we briefly review the discovery history of QC/isoQC and then discuss its regulation and function in different diseases, emphasizing the unique role of isoQC in immunotherapy. Finally, we summarize the development of inhibitors and their progress in clinical trials with the hope of providing useful insights for future investigation of QC/isoQC and targeting it in various diseases.

Deciphering the role of QPCTL in glioma progression and cancer immunotherapy

“…In chronic kidney disease, chronic treatment with QPCTL inhibitor PQ529 is a novel and effective approach for glomerulonephritis ( 39 ). Aside from cancer, targeting QPCTL has been widely studied in Alzheimer’s disease as it modified the forms of amyloid-β (Aβ) oligomers to catalyze the generation of pyroglutamate-Aβ (AβpE3), which is more neurotoxic ( 21 , 40 ). The small-molecule varoglutamstat (formerly PQ912) that inhibits the activity of QPCTL is currently in phase IIb clinical trials ( 41 ).…”

“…The glutaminyl-peptide cyclotransferase-like protein (QPCTL) belongs to a family of enzymes that catalyze the formation of pyroglutamate (pGlu) at the N-terminus of proteins by converting glutamine into pGlu residue ( 19 ), and this post-translation modification is named pyroglutamylation. The pyroglutamylation of CD47 on tumor cells is critical for its binding to SIPRα on macrophages ( 20 , 21 ). Therefore, QPCTL plays a key role in phagocytosis checkpoint immunotherapy ( 22 ).…”

Caveolin-1 promotes glioma progression and maintains its mitochondrial inhibition resistance

“…Cancer immunotherapy and immune checkpoint inhibition has become advanced therapy [ 41 ]. Understanding the characteristics of tumor-infiltrating immune cells in the glioma and the related co-working genes determines the cancer immunotherapy implications in cancer immunotherapy.…”

Emerging phagocytosis checkpoints in cancer immunotherapy

“…[360][361][362] Targeting QPCTL-mediated CD47 pyroglutamylation in CD47-SIRPα signaling: The pyroglutamylation of CD47 is essential for the binding between CD47 and SIRPα, and QPCTL is the key enzyme for pyroglytamylation of CD47. 338,363 Targeting QPCTL significantly attenuates the binding ability of CD47 to SIRPα and increases phagocytosis of tumor cells by macrophages, thus regulating tumor immunity (Fig. 7a), 50,52,364 and targeting QPCTL avoids anemia since QPCTL is not expressed on mature RBCs.…”