TY - JOUR T1 - Differential UBE2H-CTLH E2-E3 ubiquitylation modules regulate erythroid maturation JF - bioRxiv DO - 10.1101/2022.01.18.476717 SP - 2022.01.18.476717 AU - Dawafuti Sherpa AU - Judith Müller AU - Özge Karayel AU - Jakub Chrustowicz AU - Peng Xu AU - Karthik V. Gottemukkala AU - Christine Baumann AU - Annette Gross AU - Oliver Czarnezki AU - Wei Zhang AU - Jun Gu AU - Johan Nilvebrant AU - Mitchell J. Weiss AU - Sachdev S. Sidhu AU - Peter J. Murray AU - Matthias Mann AU - Brenda A. Schulman AU - Arno F. Alpi Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/01/18/2022.01.18.476717.abstract N2 - The development of haematopoietic stem cells into mature erythrocytes – erythropoiesis – is a controlled process characterized by cellular reorganisation and drastic reshaping of the proteome landscape. Failure of ordered erythropoiesis is associated with anaemias and haematological malignancies. Although the ubiquitin (UB) system is a known crucial post-translational regulator in erythropoiesis, how the erythrocyte is reshaped by the UB system is poorly understood. By measuring the proteomic landscape of in vitro human erythropoiesis models, we found dynamic differential expression of subunits of the CTLH E3 ubiquitin ligase complex that formed distinct maturation stage-dependent assemblies of structurally homologous RANBP9-and RANBP10-CTLH complexes. Moreover, protein abundance of CTLH’s cognate E2-conjugating enzyme UBE2H increased during terminal differentiation, which depended on catalytically active CTLH E3 complexes. CRISPR-Cas9 mediated inactivation of all CTLH E3 assemblies by targeting the catalytic subunit MAEA, or UBE2H, triggered spontaneous and accelerated maturation of erythroid progenitor cells including increased heme and haemoglobin synthesis. Thus, the orderly progression of human erythropoiesis is controlled by the assembly of distinct UBE2H-CTLH modules functioning at different developmental stages.Competing Interest StatementThe authors have declared no competing interest. ER -