GLUL pitches in thrombocytopoiesis by restricting ammonia accumulation during megakaryocyte maturation

Abstract

Polyploidization resulted from massive DNA synthesis is crucial for megakaryocyte maturation, while the regulatory mechanisms of cell fitness upon this special cellular process remain poorly understood. Here, we reveal that glutamine synthetase (GLUL) facilitates thrombocytopoiesis by restricting ammonia accumulation during polyploidization. GLUL is found to be distinctly expressed in platelet-producing megakaryocytes and increasingly elevated with the progression of polyploidization, and GLUL deficiency impairs megakaryocyte maturation and platelet production. Mechanistically, GLUL detoxifies ammonia derived from adenosine deaminase acting on RNA 1 (ADAR1)-mediated double-stranded RNA (dsRNA) editing in megakaryocytes undergoing polyploidization. Ammonia accumulation is observed in megakaryocytes defective in GLUL, leading to lysosomal and mitochondrial damage and even cell death. Fulvotomentoside A (FtA) is identified as a potential GLUL agonist with the capacity to promote thrombocytopoiesis in mice after radiation and chemotherapy injury. Our findings uncover the biological significance of GLUL in megakaryocyte maturation and provide a new avenue for regulating thrombocytopoiesis.