Page 24 - 2021_06-Haematologica-web

Y. Mathangasinghe et al.
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Figure 4. Hsp70 facilitates proper initiation of erythropoiesis. Heat shock protein 70 (Hsp70) is utilized as a stress sensor molecule in two fitness checkpoints to assess proteostasis deficiencies in erythroid progenitors. (A) Checkpoint 1, in essence, “gauges” and tests whether erythroblasts contain sufficient Hsp70 levels in the cytosol to block the nuclear translocation of apoptosis-inducing factor (AIF), a pro-apoptotic factor released from transiently depolarized mitochondria as a result of erythropoietin (EPO) signaling. In unhealthy cells, Hsp70 is sequestered away by protein aggregates and consequently AIF translocates into the nucleus to initiate cell death. Conversely, checkpoint 2 evaluates the ability of Hsp70 to protect GATA-1, the master regulator of erythropoiesis, from caspase 3 cleavage. This too indi- rectly evaluates the Hsp70 chaperoning capacity in early erythroblasts. Satisfaction from both tests (green) appears to be required to initiate a robust terminal dif- ferentiation process. (B) Both fitness checkpoints fail (red) in “unhealthy” cells (e.g., due to increased oxidative stress) containing high levels of misfolded and aggre- gated proteins that sequester Hsp70.
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haematologica | 2021; 106(6)