The ubiquitin ligase UBR5 suppresses proteostasis collapse in pluripotent stem cells from Huntington’s disease patients

Abstract

Induced pluripotent stem cells (iPSCs) undergo unlimited self-renewal while maintaining their potential to differentiate into post-mitotic cells with an intact proteome. As such, iPSCs suppress the aggregation of polyQ-expanded huntingtin (HTT), the mutant protein underlying Huntington’s disease (HD). Here we show that proteasome activity determines HTT levels, preventing polyQ-expanded aggregation in iPSCs from HD patients (HD-iPSCs). iPSCs exhibit high levels of UBR5, a ubiquitin ligase required for proteasomal degradation of both normal and mutant HTT. Conversely, loss of UBR5 increases HTT levels and triggers polyQ-expanded aggregation in HD-iPSCs. Moreover, UBR5 knockdown hastens polyQ-expanded aggregation and neurotoxicity in invertebrate models. Notably, UBR5 overexpression induces polyubiquitination and degradation of mutant HTT, reducing polyQ-expanded aggregates in HD-cell models. Besides HTT levels, intrinsic enhanced UBR5 expression determines global proteostasis of iPSCs preventing the aggregation of misfolded proteins ensued from normal metabolism. Thus, our findings indicate UBR5 as a modulator of super-vigilant proteostasis of iPSCs.

Ribosome and Translational Control in Stem Cells

“…Firstly, the expression of PHAX (phosphorylated adaptor for RNA export), an RBF involved in intranuclear transport of snoRNPs, is regulated during the commitment of human ESCs towards hematopoietic lineages [72]. Similarly, the E3 ubiquitin ligase UBR5 is highly expressed in human iPSCs and is downregulated during neural differentiation [73]. In addition, FBL and NCL are significantly downregulated as murine ESCs differentiate in the absence of LIF or form EBs, respectively [74,75].…”

Targeting ubiquitin protein ligase E3 component N-recognin 5 in cancer cells induces a CD8+ T cell mediated immune response

“…6 Another report indicates that as a modulator of super-vigilant proteostasis UBR5 suppresses proteostasis collapse in pluripotent stem cells from Huntington's disease patients. 7 Human UBR5 was originally identified in a screen for progestin-regulated genes in breast cancer cells. 3 It is rarely mutated in healthy somatic tissues but is mutated and overexpressed in many major cancers.…”

CRISPR/Cas9 Mediated Gene Modification Ameliorates Abnormal Phenotypes in SCA3/MJD Disease Patient Derived Induced Pluripotent Stem Cells

“…In addition, previous studies showed that no toxic aggregates formed in the polyQ diseases cell models, under the absence of external stress or proteasome stimulation culture conditions, and non-pathological ataxin3 distributed throughout nucleus and cytoplasm, while nuclear translocation occurred rapidly after the proteotoxic induction [58][59][60]. However, Moore indicated that ataxin3 expressed diffusely throughout cytoplasm and nucleus in WT-NSCs and WT-NCs, wherever, rubust ATXN3 cytoplasmic aggregates formed in large, round, juxtanuclear and occasional round ATXN3-positive inclusions in SCA3/MJD-NSCs and SCA3/MJD-NCs; Moreover, no more NIIs produced in the differentiated SCA3/MJD-NSCs and SCA3/MJD-NCs, compared with the undifferentiated SCA3/MJD-ESCs [58].…”