Immunomodulatory functions of glutaminyl cyclases QPCTL and QPCT.

Glutaminyl-peptide cyclotransferase (QPCT, QC) and its isoenzyme glutaminyl-peptide cyclotransferase-like protein (QPCTL, isoQC) are zinc-dependent enzymes that post-translationally catalyze the conversion of N-terminal glutamine or glutamate residues into pyroglutamate (pGlu). The pGlu modification impacts protein-protein interactions, enhances protein stability, and protects proteins from proteolytic degradation. QPCTL and QPCT differ in their subcellular localization, with QPCTL being retained in the Golgi apparatus and QPCT being active in secretory vesicles. Current research focuses on the impact of QPCTL-mediated pGlu formation in cancer and neurodegenerative disorders such as Alzheimer's disease. In cancer, QPCTL is a promising immunotherapy target since QPCTL-mediated CD47 pyroglutamylation prevents macrophages from phagocytosing tumor cells. Moreover, QPCTL shapes the tumor microenvironment by modulating macrophage recruitment and polarization through modification of CCL2. However, QPCTL modulates Butyrophilins on tumor cells and thereby promote their detection and killing by γδ T cells. Hence, QPCTL significantly affects cancer progression, inflammatory processes, and immune regulation. These insights highlight QPCTL's potential as a therapeutic target in oncology, metabolic diseases, and immune-mediated disorders. In this review, we highlight the role of QPCTL in tumor evasion and immune modulation. Moreover, we provide a comprehensive overview about predicted and validated substrates of QPCT/L and about the relevance of QPCT/L in various diseases.