Page 21 - 2021_06-Haematologica-web

Role of the Hsp70 chaperone in erythropoiesis
hematopoietic stem cells (Figure 3).41 It is tempting to speculate that through complexing, the CDKi mask the nuclear localization related signal of HSPA841,42 until the CDKi are degraded via stem cell factor signaling coupled to the initiation of erythropoiesis. ERK signaling, which plays a modulatory role in erythropoiesis46 also plays a role in the nuclear shuttling of Hsp70,47 but little is known about how these signals are integrated, if at all. The rodent mammalian relative of DnaJ (MRJ), an ortholog of human JDP DNAJB6, was identified from recent stem cell
AB
work48 to play a role in promoting cell quiescence by binding to a cyclin D1 inhibitor.49 The same JDP was implicated in playing a role in stem cell self-renewal.50 Whether MRJ/DNAJB6 or another JDP directs the selec- tion of clients in the CDKi-HSPA8-cyclin D1-mediated HSC proliferation pathway remains to be determined. The terminal differentiation of erythroblasts also requires cell cycle regulating cyclins. Cyclins A2 and D3 are required to control cytokinesis, erythrocyte size and number.51,52 Here too, the Hsp70 system facilitates the
Figure 2. Roles of the Hsp70 chaperone system in differentiating erythroblasts and mature erythrocytes. (A) Domain organization of the heat shock protein 70 (Hsp70) chaperone (top); the Hsp70 chaperoning cycle (bottom). Substrate binding is dictated in Hsp70 by the allosteric coupling of ATP binding and hydrolysis at the N-terminal nucleotide binding domain (NBD), which results in conformational changes at the substrate binding domain (SBD).147 The conformational cycle linked to substrate capture is defined by ATP hydrolysis driven large scale movements in the α-helical-lid domain (SBDα) that closes over the b-sandwich substrate binding subdomain (SBDb) in the ADP state, resulting in low substrate off-rates (i.e., high affinity towards bound substrates).30 J-domain proteins (JDP) select substrates for Hsp70. Concomitant interactions of the Hsp70 (in ATP state) with JDP and substrate result in increased stimulation of ATP hydrolysis trapping the substrate in Hsp70. Subsequently, nucleotide exchange factors (NEF) induce ADP dissociation from Hsp70 allowing ATP rebinding, which triggers substrate release to complete Hsp70 cycle. Substrate unfolding and refolding is facilitated by multiple cycles of substrate binding and release. Hsp70 recognizes a highly degenerative and frequently occurring peptide motif enriched with five hydrophobic amino acids, flanked by preferentially positively charged amino acids (statistically occurring in every 30-40 residues in polypeptide chains).148 Such hydrophobic motifs are typically buried inside a natively folded protein, but become exposed in unfolded or misfolded con- formers, which allow the Hsp70 machinery to discriminate between natively folded and unfolded/misfolded/aggregated substrates.30 (B) Expression profiles of select- ed chaperone systems in different stages of erythropoiesis from quantitative proteomics data.3,5 The black dotted line represents the median relative abundance of non-hemoglobin (Hb) proteins in each cell type. The cytosolic Hsp70/110, Hsp60, and Hsp90 initially represent about 1% of the total proteome in erythroid progenitor stages. Their abundance, however, gradually decreases as the proportion of Hb increases during erythropoiesis, but much less so than ribosomes and histones. Below, multifaceted functions of the Hsp70 chaperone system at major steps of red blood cell generation. Ability to synthesize proteins is lost in mature erythrocytes. Protein degradation capacity is largely reduced in mature erythrocytes. A selective Hsp70 system seems to drive protein repair in terminally differentiated erythro- cytes. PQC: protein quality control.
haematologica | 2021; 106(6)
1523