Wdr26 regulates nuclear condensation in developing erythroblasts

Abstract

Mammalian red blood cells lack nuclei. The molecular mechanisms underlying erythroblast nuclear condensation and enucleation, however, remain poorly understood. Here we show that Wdr26, a gene upregulated during terminal erythropoiesis, plays an essential role in regulating nuclear condensation in differentiating erythroblasts. Loss of Wdr26 induces anemia in zebrafish and enucleation defects in mouse erythroblasts because of impaired erythroblast nuclear condensation. As part of the glucose-induced degradation-deficient ubiquitin ligase complex, Wdr26 regulates the ubiquitination and degradation of nuclear proteins, including lamin B. Failure of lamin B degradation blocks nuclear opening formation leading to impaired clearance of nuclear proteins and delayed nuclear condensation. Collectively, our study reveals an unprecedented role of an E3 ubiquitin ligase in regulating nuclear condensation and enucleation during terminal erythropoiesis. Our results provide mechanistic insights into nuclear protein homeostasis and vertebrate red blood cell development.

GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme

“…In particular, the different Gid7 orthologs form distinct supramolecular assemblies ( Figure 6 ). We speculate that the unique assemblies define distinct functions, as implied by varying phenotypic alterations upon their individual mutation ( Bauer et al., 2018 ; Nassan et al., 2017 ; Skraban et al., 2017 ; Zhen et al., 2020 ).…”

Targeted Regulation of Nuclear Lamins by Ubiquitin and Ubiquitin-Like Modifiers

“…Recently, Zhen and colleagues reported that during terminal erythropoiesis, which is characterized by erythroblast nuclear condensation and enucleation, Wdr26, a core component of the CTLH E3 ubiquitin ligase complex, targets several nuclear proteins, including B-lamins, for ubiquitination and proteasomal degradation [ 73 ]. Interestingly, the expression levels of lamin A/C were mostly unaffected by Wdr26 or by depletion of Rmnd5a, another core component of the CTLH E3 ligase complex which cooperates with Wdr26 in the regulation of B-lamins.…”

GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme

“…Physiological importance of the CTLH E3 is underscored by developmental defects in flies, fish, frogs, and mammals arising from genetic deletions or mutations of its subunits (Han et al, 2016;Javan et al, 2018;Nguyen et al, 2017;Pfirrmann et al, 2015;Soni et al, 2006;Wei et al, 2019;Zavortink et al, 2020;Zhen et al, 2020). Yet, how Gid7 or its human orthologs regulate GID and CTLH E3 ligase complexes is unknown.…”