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Y. Mathangasinghe et al.
erythrocytes also showed a dramatic decrease in the lev- els of aggregated Hb. The authors speculated that the observed decrease in α-globin aggregation resulted from an increase in eIF2α phosphorylation, which reduced the production of globin chains (approximately 20% and 40% reduction in α- and b-globin, respectively, compared to control animals).27 However, the steady-state α-glo- bin:b-globin ratio in the soluble protein fraction, in which the aggregate prone α-globin was still largely in excess, did not change between Hbbth3/+ and Hbbth3/+ Ube2o−/− cells. A closer look at the chaperone levels in the Hbbth3/+ Ube2o−/− erythrocytes suggests an alternative explanation. The study shows that the deletion of UBE2O resulted in ele- vated levels of AHSP. Similarly, the Hsp70 and Hsp90 chaperone systems were also induced in these cells.27 Such chaperone inductions could boost the protein repair capacity consequently leading to the observed decrease in α-globin precipitation in Hbbth3/+ Ube2o−/− erythroblasts despite defects in degrading excess α-globin. The moder- ate decrease in α-globin synthesis may also help reduce the burden on PQC machineries contributing to the remarkable rescue of erythroblasts in the Hbbth3/+ Ube2o−/− animals. Based on the findings from our proteomics data analysis (Figure 5), we speculate that the degradation of a certain amount of damaged proteins, despite the inability to replace them, might be tolerated and perhaps advanta- geous for the long-term survival of mature erythrocytes under healthy conditions. However, in unhealthy ery- throblasts (e.g., early b-thalassemic erythroblasts108), a strong induction of the UPS due to stress could generate an aberrant PQC condition where even foldable conform- ers of proteins might be partitioned towards rapid degra- dation.101 Such a condition could disrupt the fine balance between protein repair and clearance in these cells (Figure 5G). A careful study of the potential misregulation of PQC pathways in erythroblasts is required to fully com- prehend the underlining mechanism of pathology in b- thalassemia. It is tempting to speculate that even slight increases in the levels of certain Hsp70 machineries at pre- or very early stages of erythropoiesis may favorably tilt the folding equilibrium of globin chains and minimize the formation of cytotoxic Hb aggregates. Such chaper- one manipulations at clinical level could result in reducing the symptoms of b-thalassemia.
Hsp70, a key modulator of inflammation in sickle cell disease?
Sickle cell disease (SCD) is another autosomal recessive genetic disorder associated with chronic anemia. SCD results from massive cyclic-polymerization of a structurally aberrant variant of adult Hb S (HbS) under hypoxic condi- tions. The resulting HbS fibers deform mature erythrocytes into rigid “sickle” shaped cells that aggregate and readily undergo premature destruction in the vasculature. Whether these conditionally formed reversible protein fibers (distinct from amyloid-type fibers formed e.g., in neurodegenerative disorders) trigger any proteostasis insult involving the Hsp70 system is unknown. The Hsp70 chap- erone, however, may play an important role in activating the inflammatory response in SCD.109,110 Stressed cells have been observed to secrete Hsp70 into the extracellular matrix.109 Immune cells generate specific peptides from secreted Hsp70 that act as key mediators of stress-induced inflammation.111-113 A considerable buildup of circulating Hsp70 levels have been detected in patients with SCD109
suggesting that there is an active secretion of Hsp70 by blood cells. Under hypoxic conditions, sickled erythrocytes show differential recruitment of the stress-inducible HSPA1A to the cell membrane,114 possibly representing an early step in this secretion process. Interestingly, a similar observation was recently noted in b-thalassemia interme- dia.115 Together, the observations suggest that the high lev- els of extracellularly circulating Hsp70 may serve as an important immune modulator that trigger inflammation in these hemoglobinopathies, leading to increased red blood cell destruction by macrophages.
Haploinsufficiency of Hsp70 associated with myelodysplastic syndromes
Myelodysplastic syndromes (MDS) are a heteroge- neous, but closely related group of hematopoietic malig- nancies characterized by ineffective erythropoiesis lead- ing to peripheral blood cytopenias.116 The mitochondria localized HSPA9 is strongly implicated as a protein that contributes to MDS. The HSPA9 locus (5q31.2) is fre- quently deleted in patients with MDS, leading to a hap- loinsufficiency of this chaperone.117 Recent work showed that mutating HSPA9 causes an MDS-like phenotype in zebrafish118 and a knockdown in rodents results in con- siderable delay in erythroid progenitor maturation.58 HSPA9 is implicated in the pathogenesis of MDS at two levels. First, the haploinsufficiency of the chaperone may contribute to the phenotype as a result of altered mito- chondrial import and refolding of heme-synthesis enzymes required for heme biogenesis during erythro- poiesis.55 Second, a decrease in HSPA9 could activate p53, a nuclear transcription factor, resulting in cell cycle arrest and premature apoptosis of hematopoietic progen- itor cells.57
Further, a recent study demonstrated that defects in EPO induced nuclear translocation of Hsp70 in erythrob- lasts could also be an important driver of these disorders.119 The ineffective erythropoiesis observed in MDS could largely be reversed by protecting GATA-1 from caspase 3 cleavage using an Hsp70 variant (lacking the nuclear export signal) that accumulates in the nucle- us.119 Protein aggregates containing aberrant p53 (as in cancer cells)120,121 have been detected in erythroblasts in some forms of MDS.122 These aggregates could conceiv- ably sequester Hsp70, thus triggering ineffective erythro- poiesis in a similar mechanism to that in b-thalassemia. Alternatively, defective EPO signaling or/and other mechanisms affecting nuclear transportation of proteins, could lead to the Hsp70 trafficking defect observed in MDS.119
Hsp70 is a modifier of polycythemia vera
Polycythemia vera is a hyperproliferative disorder char- acterized by increased synthesis of red blood cells result- ing in hyperviscosity of whole-blood. Recent proteomic studies on polycythemia vera have shown that increased levels of Hsp70 along with Hsp90 stabilize JAK2 kinase. This triggers a prolonged aberrant activation of the kinase, which results in massive proliferation of erythroid progenitors and abnormal stimulation of erythro- poiesis.123-126 Inhibition of either Hsp70 or Hsp90 has been demonstrated to promote the apoptosis of the abnormal- ly proliferating erythroid progenitors and is currently being investigated as a potential therapeutic approach to delay the progression of this disease in humans.123,126
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haematologica | 2021; 106(6)