TY - JOUR

T1 - Modular UBE2H-CTLH E2-E3 complexes regulate erythroid maturation

AU - Sherpa, Dawafuti

AU - Mueller, Judith

AU - Karayel, Özge

AU - Xu, Peng

AU - Yao, Yu

AU - Chrustowicz, Jakub

AU - Gottemukkala, Karthik V

AU - Baumann, Christine

AU - Gross, Annette

AU - Czarnecki, Oliver

AU - Zhang, Wei

AU - Gu, Jun

AU - Nilvebrant, Johan

AU - Sidhu, Sachdev S

AU - Murray, Peter J

AU - Mann, Matthias

AU - Weiss, Mitchell J

AU - Schulman, Brenda A

AU - Alpi, Arno F

N1 - © 2022, Sherpa, Mueller, Karayel et al.

PY - 2022/12/2

Y1 - 2022/12/2

N2 - The development of haematopoietic stem cells into mature erythrocytes - erythropoiesis - is a controlled process characterized by cellular reorganization and drastic reshaping of the proteome landscape. Failure of ordered erythropoiesis is associated with anaemias and haematological malignancies. Although the ubiquitin system is a known crucial post-translational regulator in erythropoiesis, how the erythrocyte is reshaped by the ubiquitin 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 maturation stage-dependent assemblies of topologically homologous RANBP9- and RANBP10-CTLH complexes. Moreover, protein abundance of CTLH's cognate E2 ubiquitin conjugating enzyme UBE2H increased during terminal differentiation, and UBE2H expression depended on catalytically active CTLH E3 complexes. CRISPR-Cas9-mediated inactivation of CTLH E3 assemblies or UBE2H in erythroid progenitors revealed defects, including spontaneous and accelerated erythroid maturation as well as inefficient enucleation. Thus, we propose that dynamic maturation stage-specific changes of UBE2H-CTLH E2-E3 modules control the orderly progression of human erythropoiesis.

AB - The development of haematopoietic stem cells into mature erythrocytes - erythropoiesis - is a controlled process characterized by cellular reorganization and drastic reshaping of the proteome landscape. Failure of ordered erythropoiesis is associated with anaemias and haematological malignancies. Although the ubiquitin system is a known crucial post-translational regulator in erythropoiesis, how the erythrocyte is reshaped by the ubiquitin 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 maturation stage-dependent assemblies of topologically homologous RANBP9- and RANBP10-CTLH complexes. Moreover, protein abundance of CTLH's cognate E2 ubiquitin conjugating enzyme UBE2H increased during terminal differentiation, and UBE2H expression depended on catalytically active CTLH E3 complexes. CRISPR-Cas9-mediated inactivation of CTLH E3 assemblies or UBE2H in erythroid progenitors revealed defects, including spontaneous and accelerated erythroid maturation as well as inefficient enucleation. Thus, we propose that dynamic maturation stage-specific changes of UBE2H-CTLH E2-E3 modules control the orderly progression of human erythropoiesis.

KW - Humans

KW - Proteomics

KW - Erythropoiesis

KW - Erythrocytes

KW - Proteome

KW - Ubiquitin

KW - Ubiquitin-Conjugating Enzymes/genetics

KW - Microtubule-Associated Proteins

KW - Guanine Nucleotide Exchange Factors

U2 - 10.7554/eLife.77937

DO - 10.7554/eLife.77937

M3 - Journal article

C2 - 36459484

VL - 11

JO - eLife

JF - eLife

SN - 2050-084X

ER -