Autophagy and Its Lineage-Specific Roles in the Hematopoietic System

Abstract

Autophagy is a dynamic process that regulates the selective and nonselective degradation of cytoplasmic components, such as damaged organelles and protein aggregates inside lysosomes to maintain tissue homeostasis. Different types of autophagy including macroautophagy, microautophagy, and chaperon-mediated autophagy (CMA) have been implicated in a variety of pathological conditions, such as cancer, aging, neurodegeneration, and developmental disorders. Furthermore, the molecular mechanism and biological functions of autophagy have been extensively studied in vertebrate hematopoiesis and human blood malignancies. In recent years, the hematopoietic lineage-specific roles of different autophagy-related (ATG) genes have gained more attention. The evolution of gene-editing technology and the easy access nature of hematopoietic stem cells (HSCs), hematopoietic progenitors, and precursor cells have facilitated the autophagy research to better understand how ATG genes function in the hematopoietic system. Taking advantage of the gene-editing platform, this review has summarized the roles of different ATGs at the hematopoietic cell level, their dysregulation, and pathological consequences throughout hematopoiesis.

Figure 1

Schematic representation of the different types of autophagy. Selective macroautophagy is a strictly regulated cytosolic cargo degradation pathway for the removal of excess ribosomes—ribophagy (a), intracellular pathogens—xenophagy (b), lipid droplets—lipophagy (c), superfluous protein aggregates—aggrephagy (d), polluted mitochondria—mitophagy (e), dispensable peroxisomes—pexophagy (f), and ferritin iron—ferritinophagy (g). Under stress, tumorigenesis, anticancer therapy, and nonselective macroautophagy are initiated with the isolation of the phagophore membrane, autophagosome formation, maturation, and degradation in the lysosome. Likewise, macroautophagy and microautophagy can be selective, while most microautophagy is the nonselective and bulk degradation of cargo molecules. Chaperone-mediated autophagy (CMA) is the translocation of the motif-bearing substrate molecules to the lysosomal membrane, whereas the lysosomal hydrolases degraded the proteins and release amino acids. During LAP, a common form of noncanonical macroautophagy, ATGs from the PIK3 complex, ATG5-ATG12, and LC3 conjugation system incorporated in phagolysosome formation and its degradation without the ULK1 complex autophagy.

Figure 2

Macroautophagy and its role in hematopoiesis. During macroautophagy, AMPK activates the ULK1 complex and consequently induces the membrane isolation process where PI3Ks and ATG9 take part as positive regulators and enable autophagosome formation with the aid of ATG12-ATG5 and the LC3 conjugation systems. The ATG5–ATG12–ATG16L1 complex induces LC3 conjugation, whereas LC3 is cleaved by ATG4 protease to form LC3-I, and cytosolic LC3-1 is further conjugated with PE to form LC3-II. Afterward, autophagosomes come in contact with the lysosome which has the hydrolase enzymatic activity to fuse with autophagosome to form autolysosome for cytosolic cargo degradation. The normal state of autophagic activity is essential for the maintenance of blood cell homeostasis. Defective autophagy results in imbalanced hematopoiesis and impeded HSCs' self-renewal, leading to the generation of malignant blood cell types.

Figure 3

Autophagy-related genes involved in hematopoietic differentiation. Schematic representation indicated that different autophagy and marker proteins play vital roles during hematopoiesis. Specific stages of hematopoietic cell differentiation require the putative mechanistic involvement of different autophagy genes as well as multiple autophagy factors. HSPC: hematopoietic stem and progenitor cell; CMP: common myeloid progenitor; CLP: common lymphoid progenitor; GMP: granulocyte-macrophage progenitor; NK: natural killer cell; PP: multipotent progenitor.

Figure 4

Expression of different autophagy markers in hematopoietic cells and AMLs. Schematic representation indicated the expression level of different ATG genes, autophagy-related factors, and different ATG receptors in both hematopoietic cells and various types of acute myeloid leukemia. PMN: polymorphonuclear cells; MPP: multipotential progenitors; MLL: mixed-lineage leukemia; AML t(15;17): AML with t(15;17); AML inv(16)/t(16;16): AML with inv(16)/t(16;16); AML t(11q23)/MLL: AML with t(11q23)/MLL; AML complex: AML with complex aberrant karyotype. Data were generated from normal human samples and samples from the human AML cells using microarray-based gene expression profiling. The “BloodSpot” (https://servers.binf.ku.dk/bloodspot/) database was used to generate the hierarchical differentiation tree.