Pyruvate kinase synthesis and degradation by normal and pathologic cells during erythroid maturation

Abstract

Mature erythrocytes contain a specific isozyme of pyruvate kinase (R- PK) while immature erythroblasts coexpress R-PK and another isozyme, M2- PK. To determine what roles degradation and decreasing of synthesis played in the disappearance of M2-PK during erythroid maturation, M2-PK and R-PK synthesis and degradation were studied in erythroblasts from fetal liver and blood BFU-E-derived erythroblasts from healthy subjects, an erythroleukemic patient, and a patient with an erythrocyte PK hyperactivity associated with M2-PK persistence in mature erythrocytes. In normal erythroblasts, R-PK synthesis was constant throughout erythroid maturation, whereas M2-PK synthesis decreased to the point of becoming undetectable. R-PK degradation was very low, while M2-PK degradation was more pronounced and steady during erythroid maturation. In leukemic erythroblasts, total protein turnover was higher than in normal cells, but the M2-PK degradation rate was lower. In erythroblasts from the patient with M2-PK persistence in mature erythrocytes, M2-PK synthesis did not decline with cell maturation. In conclusion, our results emphasize the importance of the decrease of M2- PK synthesis in the disappearance of M2-PK during erythroid maturation. Further studies of patients with pathologic persistence of M2-PK synthesis will help in the understanding of this event involved in erythroid maturation.

Novel potential therapeutics to modify iron metabolism and red cell synthesis in diseases associated with defective erythropoiesis

“… 46 Pharmacological induction of protein-targeted quality control pathways and autophagy to eliminate relevant unstable proteins could be potentially beneficial in patients with BT. 47 , 4 8 As mTORC1 inhibits autophagy, systemic treatment with the mTORC1 inhibitor rapamycin reduces α-globin precipitates and lessens pathologies in BT mice. 49 These findings may allow investigation of additional pathways that can be regulated by drugs for amelioration of BT symptoms.…”