Nuclear Ubiquitin-Proteasome Pathways in Proteostasis Maintenance

Abstract

Protein homeostasis, or proteostasis, is crucial for the functioning of a cell, as proteins that are mislocalized, present in excessive amounts, or aberrant due to misfolding or other type of damage can be harmful. Proteostasis includes attaining the correct protein structure, localization, and the formation of higher order complexes, and well as the appropriate protein concentrations. Consequences of proteostasis imbalance are evident in a range of neurodegenerative diseases characterized by protein misfolding and aggregation, such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis. To protect the cell from the accumulation of aberrant proteins, a network of protein quality control (PQC) pathways identifies the substrates and direct them towards refolding or elimination via regulated protein degradation. The main pathway for degradation of misfolded proteins is the ubiquitin-proteasome system. PQC pathways have been first described in the cytoplasm and the endoplasmic reticulum, however, accumulating evidence indicates that the nucleus is an important PQC compartment for ubiquitination and proteasomal degradation of not only nuclear, but also cytoplasmic proteins. In this review, we summarize the nuclear ubiquitin-proteasome pathways involved in proteostasis maintenance in yeast, focusing on inner nuclear membrane-associated degradation (INMAD) and San1-mediated protein quality control.

Rapid Internalization and Nuclear Translocation of CCL5 and CXCL4 in Endothelial Cells

“…Other cytokine (-like) or danger-associated molecules have intra- and extracellular actions (reviewed in [ 44 ]), and it is conceivable that CXCL4 might act in a similar fashion. Alternatively, chemokine uptake by EC might serve to maintain or regulate local chemokine levels in a fashion similar to the ACKRs [ 44 , 45 ] and might be targeted to the nucleus for proteasomal degradation [ 46 ].…”

ALDH1A3 Segregated Expression and Nucleus-Associated Proteasomal Degradation Are Common Traits of Glioblastoma Stem Cells

“…By demonstrating the abundance of ALDH1A3 peptides naturally occurring in human GSCs, our study not only provides such evidence but also provides further insights into the mechanism of ALDH1A3 turnover via proteasome-dependent breakdown in the nucleus. Although the role of the nucleus-based quality control of cytoplasmic proteins in mammalian cells has not yet been fully elucidated, the principal possibility of cytoplasmic proteins degradation in the nucleus has been shown in human cells [ 32 , 33 ]. Although we favor the interpretation that proteasomal degradation in the nucleus is the mechanism for generating truncated ALDH1A3 peptides, it also cannot be ruled out that ALDH1A3 fragments may be hauled to the nucleus by some nuclear proteins or translocated by passive diffusion [ 34 ].…”

Brain Cell Type-Specific Nuclear Proteomics Is Imperative to Resolve Neurodegenerative Disease Mechanisms

“…NIID is caused by a CGG repeat expansion in the 5′UTR of the NOTCH2NLC (a gene that plays roles in neuronal development by regulating Notch signaling), was discovered in Japanese populations and recently replicated in a European ancestry cohort (Nakamura et al, 2020 ). The NIID intranuclear inclusions are immunoreactive for ubiquitin, p62/SQSTM1, SUMO1, FUS, and OPTN, suggesting that nuclear ubiquitin-mediated proteasome pathways are normally functioning in the nucleus and those pathways are aberrantly stimulated in NIID (Pountney et al, 2003 ; Franic et al, 2021 ). Nuclear inclusions are also seen in other conditions including FTLD-TDP, HD, and others (Sieradzan et al, 1999 ; Woulfe et al, 2001 ).…”