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The function of QC/isoQC in diseases. (a) Function of QC/isoQC in cancer: IsoQC catalyzes the pyroglutamylation of CD47 and contributes to the interaction with the CD47-SIRPα axis and finally leads to the cancer cell immune surveillance evasion. Targeting isoQC by SEN177 or other molecules inhibits the pyroglutamylation of CD47, thus CD47 cannot interact with SIRPα, and cancer cells are phagocyted by the macrophages. The pyroglutamylation of CCL2 upregulates CCL2 expression and recruits more immune cells such as DCs, monocytes, and T cells into the tumor microenvironment. The pyroglutamylation of CX3CL1 is critical for its binding to CX3CR and blocks the CX3CL pyroglutamylation leading to the degradation of the protein and affecting its binding to receptors. The basic function of QC/isoQC is to catalyze the target protein N terminal pyroglutamine and protect it from degradation. (b) Function of QC in neuro diseases: QC is primarily and highly expressed in the brain including the hippocampus and cortex and other peripheral tissues. It converts beta-amyloid (Aβ) N-terminal peptides at position 3 or 11 into pGlu. Abnormally upregulation of QC in AD functions as a key inducer in the initiation of AD by catalyzing the generation of different mediators such as pyroglutamylation of Aβ and CCL2, which are the main causes of neurotoxicity and inflammation. Small molecules such as PBD-150 and PQ-912 inhibit QC activity and reduce the syndrome of AD, PQ-912 is in a Phase II clinical trial now. In Huntington’s disease, the pyroglutamylation catalyzed by QCs leads to the aggregation of huntingtin (HTT) protein and finally leads to Huntington’s disease. A small molecule such as SEN177 targeting QC/isoQC rescues Huntington’s disease phenotypes efficiently and reduce HTT protein aggregation.
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