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Role of the Hsp70 chaperone in erythropoiesis
Haploinsufficiency of Hsp70 modulates Diamond Blackfan anemia
Diamond Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome resulting from ineffective erythropoiesis.127 In this disease, erythroid differentiation arrests between BFU-E and CFU-E stages.128 More than 70% of the cases of DBA occur due to haploinsufficiency of genes that encode for the small and large ribosomal subunit proteins.129-131 The defective ribosome biogenesis triggers ineffective erythropoiesis in part due to the decreased production of GATA-1.132 This is further pro- moted by imbalances in globin chain and heme synthesis leading to α-globin aggregation and induction of oxida- tive stress in erythroblasts133 similar to b-thalassemia. Additionally, in DBA associated with RPL11, but not RPL19 haploinsufficiency, the Hsp70 chaperone is consid- erably degraded in the erythroblasts via the UPS.133,134 The reason for the rapid degradation of Hsp70 in some per- mutations of this disorder remains unclear. Recent work shows that aberrations in chromatin organization result- ing from low levels of the global chromatin organizer SATB1 prevents the induction of Hsp70 in early erythrob- lasts in DBA.135 Together, these observations suggest that the differential Hsp70 expression and degradation rates may have considerable effect on red blood cell viability, differentiation and Hb biogenesis, thus partly explaining the variability in the observed phenotypes of DBA. Remarkably, the restoration of Hsp70 levels in affected erythroblasts inhibits premature apoptosis and substan- tially restores erythropoiesis in DBA,133,134 thus providing an important therapeutic avenue for the treatment of this blood disorder.
A predicted pathological role for Hsp70 in congenital sideroblastic anemias
Congenital sideroblastic anemias (CSA) are inherited rare blood disorders characterized by erythroblasts dis- playing ring sideroblasts formed by the pathological dep- ositions of iron in mitochondria. Patients with CSA show a significant reduction in the regeneration of erythrocytes leading to anemic conditions. The ineffective erythro- poiesis in CSA is caused by defects in iron-sulfur cluster biogenesis essential for a broad range of cellular func- tions. Patients with CSA show mutations in genes direct- ly (e.g., GLRX5, ABCB7)136,137 and indirectly (e.g., HSPA9)138,139 associated with this biosynthetic pathway. It is important to note that the ring sideroblasts are uncom- mon in MDS cases that are also associated with HSPA9 deletion mutations (see above), but whether this is due to
an epistatic suppression by another modifier remains to be investigated.138 As in CSA, HSPA9 may also play an indirect role in some forms of dyserythropoietic anemias that are also characterized by pathological iron-loading defects and ineffective erythropoiesis140 and warrants fur- ther investigation.
Age-associated anemia
Aging is attributed to a decline in hematopoiesis with high incidents of anemia.141 The viability and self-renewal of HSC/early erythroid progenitors depend on maintain- ing robust PQC activity and high levels of Hsp70.142,143,144 These abilities decline in stem cells during aging.145,146 As a consequence, Hsp70-mediated functions such as mainte- nance of erythroid dormancy, cell cycle quiescence and cell cycle entry may breakdown leading to an age-related exhaustion of HSC.
Concluding remarks
Recent findings have considerably broadened our under- standing of the multifaceted roles of Hsp70 in erythrocyte differentiation and how deficiencies in its activity modify several blood disorders in humans. The tuning of the Hsp70 chaperone system to cater to different PQC needs during erythropoiesis sheds extremely valuable insight on cell repair and viability and provides a conceptual frame- work for investigating chaperone-based therapeutic avenues for a wide spectrum of blood disorders.
Disclosures
No conflicts of interest to disclose.
Contributions
NBN conceptualized the work. BF, PG and NBN analyzed published proteomics data. YM, BF, SJ, PG and NBN wrote and edited the manuscript.
Acknowledgements
We thank Andrew Perkins (Australian Center for Blood Diseases) David Ron (Cambridge Institute for Medical Research) for critically reading the manuscript.
Funding
This work was supported by a special Recruitment Grant from the Monash University Faculty of Medicine Nursing and Health Sciences with funding from the State Government of Victoria and the Australian Government to NBN.
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