Normal and disordered reticulocyte maturation

Abstract

Purpose of review: Reticulocyte remodeling has emerged as an important model for the understanding of vesicular trafficking and selective autophagy in mammalian cells. This review covers recent advances in our understanding of these processes in reticulocytes and the role of these processes in erythroid development.

Recent findings: Enucleation is caused by the coalescence of vesicles at the nuclear-cytoplasmic junction and microfilament contraction. Mitochondrial elimination is achieved through selective autophagy, in which mitochondria are targeted to autophagosomes, and undergo subsequent degradation and exocytosis. The mechanism involves an integral mitochondrial outer membrane protein and general autophagy pathways. Plasma membrane remodeling, and the elimination of certain intracellular organelles occur through the exosomal pathway.

Summary: Vesicular trafficking and selective autophagy have emerged as central processes in cellular remodeling. In reticulocytes, this includes enucleation and the elimination of all membrane-bound organelles and ribosomes. Ubiquitin-like conjugation pathways, which are required for autophagy in yeast, are not essential for mitochondrial clearance in reticulocytes. Thus, in higher eukaryotes, there appears to be redundancy between these pathways and other processes, such as vesicular nucleation. Future studies will address the relationship between autophagy and vesicular trafficking, and the significance of both for cellular remodeling.

Figure 1

Normal reticulocyte maturation. Four steps in reticulocyte maturation are shown, in roughly sequential order. 1) Iron import-ransferrin receptor recycling. Iron-loaded transferrin bound to the transferrin receptor is in internalized via clatharin-mediated endocytosis into the early endosomal compartment. After acidification of the endosome and release of iron from transferrin, transferrin-transferrin receptor complex recycles to the cell surface. 2) Enucleation. Vesicles coalesce at the nuclear cytoplasmic junction, creating a new limiting membrane. The sides are pinched inwards by the combined action of vesicle trafficking and microfilaments. 3) Mitochondrial clearance. Vesicles are recruited and surround mitochondria in a process that requires NIX, and is partially dependent on autophagy. Mitochondria are subsequently degraded and eliminated by exocytosis. 4) Secretion of exosomes. Membrane is lost and transferrin receptor and other membrane proteins are downregulated through the MVE-exosomal pathway. MVE are generated by membrane invagination in late endosomes. Intraluminal vesicles are released into the extracellular space by exocytosis.