CAPRIN2 RNA-binding protein contributes to balance erythroid production: Implications in the fine-tuning of proteostasis during erythropoiesis

Abstract

Erythropoiesis is a process that requires tight control of gene transcription, mRNA stability, and protein synthesis and degradation. These regulatory layers adapt dynamically to developmental needs and physiological stresses, ensuring precise control of erythroid production. Ribosomopathies, such as Diamond-Blackfan anemia (DBA), are characterized by defects in ribosome function. Zooming in on erythroid precursors, ribosomopathies lead to dysregulated translation of mRNAs encoding specific and essential erythropoietic genes, including master transcription factors such as GATA1. This causes defective maturation and increased apoptosis of erythroid progenitors, and consequently, anemia. Beyond ribosomal proteins, RNA-binding proteins have been put forward as an additional and targeted checkpoint regulating cellular proteostasis. CAPRIN2, which is present in neurons and erythroid cells, is one such RNA-binding protein, involved in RNA translation regulation and its levels rise during terminal erythroid differentiation. Overexpression of CAPRIN2 in Chinese hamster ovary (CHO) cells causes reduced growth, cell cycle arrest, and apoptosis. Here, we demonstrate that GATA1 potentially regulates Caprin2 transcription, and that Caprin2 loss boosts erythroid production and maturation during gestation and adulthood, a phenomenon that is enhanced in situations of stress erythropoiesis. Our results provide new insight into the role of CAPRIN2 in erythropoiesis. We hypothesize that it regulates the translation of key mRNAs during erythropoiesis. We propose that CAPRIN2 is involved in the balance of erythroid production and that its manipulation may control erythroid production, offering a potential and promising approach to manage altered erythropoiesis.