Abstract
Mammalian erythroid cells undergo extensive organelle and protein remodeling during erythropoiesis. The transcriptome and proteome of ubiquitin E3 ligases change dynamically during erythroid differentiation, yet mechanisms beyond E3 activity remain unclear. Here, we identify that tripartite motif-containing protein 10α (TRIM10α), an erythroid- and stage-specific E3 ligase, as crucial for stepwise erythroid maturation. TRIM10α self-association to localize on erythroblast surfaces, binding extracellular complement C1q, which facilitates pyrenocyte encapsulation and macrophage recognition. Surface C1q interacts with EpoR to promote lysosomal degradation, and its depletion prolongs Epo signaling. Notably, cytosolic TRIM10α enhances hemoglobin (Hb) maturation and sequesters Hb aggregates under oxidative conditions. Ultimately, TRIM10α self-ubiquitination and its binding to p62 are anticipated to lead to TRIM10α degradation, promoting the removal of Hb aggregates via autophagy. In contrast to TRIM10α, an alternatively spliced TRIM10β, which is barely expressed in human tissues and cells, forms deleterious aggregates, suggesting that evolutionary suppression of TRIM10β supports erythroid homeostasis. Our findings propose that aberrant TRIM10 expression drives erythroid-related diseases and highlight TRIM10 as a potential biomarker or therapeutic target.