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The Hsp70 chaperone system: distinct roles in erythrocyte formation and maintenance
Ferrata Storti Foundation
Haematologica 2021 Volume 106(6):1519-1534
Yasith Mathangasinghe,1 Bruno Fauvet,2 Stephen M. Jane,3,4 Pierre Goloubinoff2 and Nadinath B. Nillegoda1
1Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia; 2Department of Plant Molecular Biology, Lausanne University, Lausanne, Switzerland; 3Central Clinical School, Monash University, Prahran, Victoria, Australia and 4Department of Hematology, Alfred Hospital, Monash University, Prahran, Victoria, Australia
ABSTRACT
Erythropoiesis is a tightly regulated cell differentiation process in which specialized oxygen- and carbon dioxide-carrying red blood cells are generated in vertebrates. Extensive reorganization and depletion of the erythroblast proteome leading to the deterioration of general cellular protein quality control pathways and rapid hemoglobin biogenesis rates could generate misfolded/aggregated proteins and trigger proteotoxic stresses during erythropoiesis. Such cytotoxic conditions could prevent proper cell differentiation resulting in premature apoptosis of erythroblasts (ineffective erythropoiesis). The heat shock protein 70 (Hsp70) molecular chaperone system supports a plethora of functions that help maintain cellular protein homeostasis (proteostasis) and promote red blood cell differentiation and survival. Recent findings show that abnor- malities in the expression, localization and function of the members of this chaperone system are linked to ineffective erythropoiesis in multiple hematological diseases in humans. In this review, we present latest advances in our understanding of the distinct functions of this chaperone system in differentiating erythroblasts and terminally differentiated mature erythrocytes. We present new insights into the protein repair-only function(s) of the Hsp70 system, perhaps to minimize protein degradation in mature erythrocytes to warrant their optimal function and survival in the vasculature under healthy conditions. The work also discusses the modulatory roles of this chaperone system in a wide range of hematolog- ical diseases and the therapeutic gain of targeting Hsp70.
Introduction
Cells are highly vulnerable to proteotoxic stresses during widespread remodel- ing of proteomes that typically accompany cell differentiation. Under such chal- lenging conditions, molecular chaperones that constitute an essential part of cellu- lar protein quality control (PQC) pathways, help maintain proteostasis by decreas- ing protein misfolding and aggregation, and promote cell viability.1,2 In response to cell differentiation, considerable rearrangements in cellular chaperomes have been detected,2,3 but the functional consequences of such changes largely remain enig- matic. In particular, the heat shock protein 70 (Hsp70) chaperone system is main- tained at high levels during red blood cell differentiation.3-5 Emerging data demon- strate that Hsp70 machineries have distinct functions ranging from modulating cell signaling to PQC activities at different stages of erythropoiesis. These multi- faceted roles of the Hsp70 chaperone include maintaining erythroid progenitors, assessing fitness of progenitors prior to initiating lineage specific terminal cell dif- ferentiation, supporting hemoglobin (Hb) biogenesis, counteracting proteotoxici- ties and preventing premature apoptosis of differentiating erythroblasts, and pro- moting viability of terminally differentiated erythrocytes via protein repair. Hence, the dysfunction of this chaperone system is invariably associated with ineffective erythropoiesis, which leads to chronic anemia in several hematological diseases in humans.
Correspondence:
NADINATH B. NILLEGODA
nadinath.nillegoda@monash.edu
Received: July 29, 2019. Accepted: September 25, 2020. Pre-published: April 8, 2021.
https://doi.org/10.3324/haematol.2019.233056
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