Metabolic sensor O ‐GlcNAcylation regulates megakaryopoiesis and thrombopoiesis through c‐Myc stabilization and integrin perturbation

Megakaryopoiesis and thrombopoiesis can be regulated viaO‐GlcNAc/c‐Myc axis. Inhibition ofO‐GlcNAcylation, which also occurs spontaneously during megakaryocyte differentiation, downregulates c‐Myc at posttranslational level via the promotion of c‐Myc ubiquitination and proteasomal degradation. The release of platelets via this regulatory axis partly involves the perturbation of inte grin‐β7 and integrin‐α4. AbstractMetabolic state of hematopoietic stem cells (HSCs) is an important regulator of self ‐renewal and lineage‐specific differentiation. Posttranslational modification of proteins viaO‐GlcNAcylation is an ideal metabolic sensor, but how it contributes to megakaryopoiesis and thrombopoiesis remains unknown. Here, we reveal for the first time that cellularO‐GlcNAcylation levels decline along the course of megakaryocyte (MK) differentiation from human‐derived hematopoietic stem and progenitor cells (HSPCs). Inhibition ofO‐GlcNAc transferase (OGT) that catalyzesO‐GlcNAcylation prolongedly decreasesO‐GlcNAcylation and induces the acquisition of CD34+CD41a+ MK ‐like progenitors and its progeny CD34−CD41a+/CD42b+ megakaryoblasts (MBs)/MKs from HSPCs, consequently resulting in increased CD41a+ and CD42b+ platelets. Using correlation and co ‐immunoprecipitation analyses, we further identify c‐Myc as a direct downstream target ofO‐GlcNAcylation in MBs/MKs and provide compelling evidence on the regulation of platelets by novelO‐GlcNAc/c...
Source: Stem Cells - Category: Stem Cells Authors: Tags: Tissue ‐Specific Stem Cells Source Type: research