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The ins and outs of reticulocyte maturation revisited: The role of autophagy in sickle cell disease.

Mankelow TJ, Griffiths RE, Trompeter S, Flatt JF, Cogan NM, Massey EJ, Anstee DJ - Autophagy (2016)

Bottom Line: Autophagy plays an important role in the removal of membrane bound organelles during the last stage of erythropoiesis as the enucleate reticulocyte matures into the erythrocyte.Autophagic vesicles are expelled from the reticulocyte as intact, inside-out, phosphatidylserine (PS) decorated vesicles and are subsequently removed during splenic passage.Failure to remove these vesicles causes the elevation in PS exposed red cells in Sickle Cell Disease.

View Article: PubMed Central - PubMed

Affiliation: a Bristol Institute for Transfusion Sciences, NHS Blood and Transplant , Filton , Bristol , UK.

ABSTRACT
Autophagy plays an important role in the removal of membrane bound organelles during the last stage of erythropoiesis as the enucleate reticulocyte matures into the erythrocyte. Autophagic vesicles are expelled from the reticulocyte as intact, inside-out, phosphatidylserine (PS) decorated vesicles and are subsequently removed during splenic passage. Failure to remove these vesicles causes the elevation in PS exposed red cells in Sickle Cell Disease.

No MeSH data available.


Related in: MedlinePlus

Model for the formation and release of autophagic vesicles. GYPA (extracellular domain [red circle] and intracellular domain [green square]) is internalized by endocytosis of the plasma membrane (i) to produce large GYPA-decorated vesicles (ii) that fuse with an LC3 (blue pentagon)-positive autophagosome (iii) forming a large LC3-GYPA-positive hybrid inside-out vesicle (iv). Temporary weakening of the cytoskeleton (v) allows extrusion (vi) releasing a PS-positive inside-out vesicle (vii) for phagocytosis in the spleen.
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f0001: Model for the formation and release of autophagic vesicles. GYPA (extracellular domain [red circle] and intracellular domain [green square]) is internalized by endocytosis of the plasma membrane (i) to produce large GYPA-decorated vesicles (ii) that fuse with an LC3 (blue pentagon)-positive autophagosome (iii) forming a large LC3-GYPA-positive hybrid inside-out vesicle (iv). Temporary weakening of the cytoskeleton (v) allows extrusion (vi) releasing a PS-positive inside-out vesicle (vii) for phagocytosis in the spleen.

Mentions: Reticulocytes are formed after the enucleation of orthochromatic erythroid cells during erythropoiesis and they are broadly grouped into 2 types, R1 and R2. R1 are immature reticulocytes, which are normally confined to the bone marrow for 24 h post enucleation where they become nonmotile and more mechanically stable. Once they have matured into R2 reticulocytes they are released into circulation where they take a further 24 h to mature into erythrocytes. During the whole maturation process they lose around 20% of their surface area, reduce their volume and eliminate any remaining membrane-bound cytosolic organelles. We have shown that in R2 reticulocytes the autophagic, endocytic, and exocytic processes are linked. The reduction in surface area is caused by endocytosis of plasma membrane to form a large internal GYPA-decorated vesicle, which then fuses with autophagosomes containing organelles for removal. The autophagic vesicles are extruded from the reticulocyte intact and the surface membrane of the extruded vesicle exposes the cytoplasmic domains of major red cell membrane proteins (GYPA and SLC4A1/AE1) and PS and therefore has an “inside-out” orientation. This novel process is depicted in Figure 1. It remains to be determined if this process is unique to the reticulocyte, is found in other cells where enucleation occurs (lens epithelia and keratinocytes) or is a common aspect of autophagy not previously recognized.Figure 1.


The ins and outs of reticulocyte maturation revisited: The role of autophagy in sickle cell disease.

Mankelow TJ, Griffiths RE, Trompeter S, Flatt JF, Cogan NM, Massey EJ, Anstee DJ - Autophagy (2016)

Model for the formation and release of autophagic vesicles. GYPA (extracellular domain [red circle] and intracellular domain [green square]) is internalized by endocytosis of the plasma membrane (i) to produce large GYPA-decorated vesicles (ii) that fuse with an LC3 (blue pentagon)-positive autophagosome (iii) forming a large LC3-GYPA-positive hybrid inside-out vesicle (iv). Temporary weakening of the cytoskeleton (v) allows extrusion (vi) releasing a PS-positive inside-out vesicle (vii) for phagocytosis in the spleen.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836018&req=5

f0001: Model for the formation and release of autophagic vesicles. GYPA (extracellular domain [red circle] and intracellular domain [green square]) is internalized by endocytosis of the plasma membrane (i) to produce large GYPA-decorated vesicles (ii) that fuse with an LC3 (blue pentagon)-positive autophagosome (iii) forming a large LC3-GYPA-positive hybrid inside-out vesicle (iv). Temporary weakening of the cytoskeleton (v) allows extrusion (vi) releasing a PS-positive inside-out vesicle (vii) for phagocytosis in the spleen.
Mentions: Reticulocytes are formed after the enucleation of orthochromatic erythroid cells during erythropoiesis and they are broadly grouped into 2 types, R1 and R2. R1 are immature reticulocytes, which are normally confined to the bone marrow for 24 h post enucleation where they become nonmotile and more mechanically stable. Once they have matured into R2 reticulocytes they are released into circulation where they take a further 24 h to mature into erythrocytes. During the whole maturation process they lose around 20% of their surface area, reduce their volume and eliminate any remaining membrane-bound cytosolic organelles. We have shown that in R2 reticulocytes the autophagic, endocytic, and exocytic processes are linked. The reduction in surface area is caused by endocytosis of plasma membrane to form a large internal GYPA-decorated vesicle, which then fuses with autophagosomes containing organelles for removal. The autophagic vesicles are extruded from the reticulocyte intact and the surface membrane of the extruded vesicle exposes the cytoplasmic domains of major red cell membrane proteins (GYPA and SLC4A1/AE1) and PS and therefore has an “inside-out” orientation. This novel process is depicted in Figure 1. It remains to be determined if this process is unique to the reticulocyte, is found in other cells where enucleation occurs (lens epithelia and keratinocytes) or is a common aspect of autophagy not previously recognized.Figure 1.

Bottom Line: Autophagy plays an important role in the removal of membrane bound organelles during the last stage of erythropoiesis as the enucleate reticulocyte matures into the erythrocyte.Autophagic vesicles are expelled from the reticulocyte as intact, inside-out, phosphatidylserine (PS) decorated vesicles and are subsequently removed during splenic passage.Failure to remove these vesicles causes the elevation in PS exposed red cells in Sickle Cell Disease.

View Article: PubMed Central - PubMed

Affiliation: a Bristol Institute for Transfusion Sciences, NHS Blood and Transplant , Filton , Bristol , UK.

ABSTRACT
Autophagy plays an important role in the removal of membrane bound organelles during the last stage of erythropoiesis as the enucleate reticulocyte matures into the erythrocyte. Autophagic vesicles are expelled from the reticulocyte as intact, inside-out, phosphatidylserine (PS) decorated vesicles and are subsequently removed during splenic passage. Failure to remove these vesicles causes the elevation in PS exposed red cells in Sickle Cell Disease.

No MeSH data available.


Related in: MedlinePlus