GLUL facilitates thrombocytopoiesis by restricting ammonia accumulation during megakaryocyte maturation

ABSTRACT: Polyploidization resulting from massive DNA synthesis is crucial for megakaryocyte (MK) maturation; however, the regulatory mechanisms of cell fitness on 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 MKs and increasingly elevated with the progression of polyploidization, whereas GLUL deficiency impairs MK maturation and platelet production. Mechanistically, GLUL detoxifies ammonia derived from adenosine deaminase acting on RNA 1-mediated double-stranded RNA editing in MKs undergoing polyploidization. Ammonia accumulation is observed in MKs defective in GLUL, leading to lysosomal and mitochondrial damage and even cell death. Fulvotomentoside A 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 MK maturation and provide a new avenue for regulating thrombocytopoiesis.