Autophagy as a Regulatory Component of Erythropoiesis

Abstract

Autophagy is a process that leads to the degradation of unnecessary or dysfunctional cellular components and long-lived protein aggregates. Erythropoiesis is a branch of hematopoietic differentiation by which mature red blood cells (RBCs) are generated from multi-potential hematopoietic stem cells (HSCs). Autophagy plays a critical role in the elimination of mitochondria, ribosomes and other organelles during erythroid terminal differentiation. Here, the modulators of autophagy that regulate erythroid differentiation were summarized, including autophagy-related (Atg) genes, the B-cell lymphoma 2 (Bcl-2) family member Bcl-2/adenovirus E1B 19 kDa interacting protein 3-like (Nix/Binp3L), transcription factors globin transcription factor 1 (GATA1) and forkhead box O3 (FoxO3), intermediary factor KRAB-associated protein1 (KAP1), and other modulators, such as focal adhesion kinase family-interacting protein of 200-kDa (FIP200), Ca2+ and 15-lipoxygenase. Understanding the modulators of autophagy in erythropoiesis will benefit the autophagy research field and facilitate the prevention and treatment of autophagy-related red blood cell disorders.

A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis

“…by guest www.bloodjournal.org From autophagy during the erythroid maturation processes and involves Ulk1 with the HSP90-cdc37 complex, as well as with Atg7. 16,41 Chorea-acanthocytosis red cells exhibited accumulation of Ulk1 and Atg7 in concert with delayed mitochondrial and lysosomal clearance in reticulocyte-enriched red cell fractions, supporting the proposed contribution of chorein to autophagic flux. It is of note that Atg4, which has been linked to fusion of autophagosomes to lysosomes during erythropoiesis, 70 has not been found in choreaacanthocytosis red cells, suggesting that the absence of chorein may affect initiation of autophagy related to Ulk1-or Atg-7-linked formation of autophagosomes.…”

“…The choreaacanthocytosis maturation profile at culture day 14 revealed decreased pro-erythroblasts and intermediate erythroblasts associated with increased late erythroblasts compared with healthy controls. This was associated with increased apoptosis of chorea-acanthocytosis Immunoprecipitates containing equal amounts of Ulk1 (left) or Atg7 (right) were immunoprecipitated from red cell cytosol fraction of healthy (Ctrl, control) and ChAc subjects, and Lyn kinase activity was detected using Src-specific cdc2 peptide substrate (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Data are shown as means 6 SD (n 5 6; *P , .01 compared with healthy erythrocytes).…”

“…Previous studies have shown that autophagy plays a key role in vesicle trafficking and mitochondrial clearance during late stage of erythropoiesis and in reticulocytes. 16,41,64 Thus, we used MitoTracker and LysoTracker to follow mitochondrial and lysososmal clearance in the reticulocyteenriched red cells fraction from healthy and chorea-acanthocytosis subjects incubated for 3 hours in a plasma-like medium. 41,64 As shown in Figure 5C, we found delayed mitochondria (supplemental Figure 6C) and lysosomal clearance (supplemental Figure 6D) in chorea-acanthocytosis red cells compared with those from healthy subjects.…”

“…Although choreaacanthocytosis is a rare disease, it represents an interesting model to explore and characterize new mechanisms involved in red cell proteostasis and erythroid maturation processes and may be useful in understanding other hematologic disorders characterized by altered in autophagy such as b-thalassemia. 16,17 Materials and methods…”

A novel role for nuclear factor-erythroid 2 in erythroid maturation by modulation of mitochondrial autophagy

“…34 Ours is the first report demonstrating a role for NF-E2 in erythroid maturation by affecting autophagy genes. Because NIX and ULK1 interact with partner proteins in the autophagy process, 35 their increased expression may disrupt complex formation. If the levels of interacting proteins are not raised concomitantly, ineffective complexes may be formed.…”