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.
Highlights
Maintaining a functional proteome, or proteostasis, is one of the key tasks in the cell.Proteins that are aberrant, for instance due to misfolding, inability to form complexes, or incorrect localization, can be harmful for the cell as a result of a loss of function, interference with other processes or inappropriate interactions with other components in the cell [1,2].Proteins are at risk of misfolding especially during protein synthesis and assembly into higher-order structures or protein complexes [3]
We summarize recent findings on nuclear ubiquitin-proteasome pathways that function in protein quality control (PQC) in Saccharomyces cerevisiae: The inner nuclear membrane (INM)-associated degradation (INMAD) mediated by the E3 ubiquitin ligases Asi1-3, Doa10, and anaphase-promoting complex or cyclosome (APC/C), and a nuclear pathway for degradation of misfolded proteins mediated by the E3 ubiquitin ligase San1 (Figure 1 and Table 1)
inner nuclear membrane-associated degradation (INMAD) pathways are based on the activities of three distinct E3 ubiquitin ligases: (1) integral membrane INM-localized Asi-complex that primarily targets mislocalized proteins and integral membrane orphan complex subunits, (2) integral membrane E3 ligase Doa10, which localizes to the endoplasmic reticulum (ER) membrane and is best described for its role in degradation of misfolded proteins via ERAD, and (3) nuclear E3 ligase APC/C, which controls the levels of integral membrane SUN-domain protein at the nuclear envelope (NE)
Summary
Maintaining a functional proteome, or proteostasis, is one of the key tasks in the cell. The main pathway for degradation of misfolded proteins is the ubiquitin-proteasome system. We summarize recent findings on nuclear ubiquitin-proteasome pathways that function in PQC in Saccharomyces cerevisiae: The INM-associated degradation (INMAD) mediated by the E3 ubiquitin ligases Asi, Doa, and APC/C, and a nuclear pathway for degradation of misfolded proteins mediated by the E3 ubiquitin ligase San. Integral membrane Asi-substrates include proteins mislocalized to the INM, orphan subunits of unassembled proteins complexes, and temperature-sensitive (ts) mutants. Integral membrane E3 ligase Doa localizes to both the endoplasmic reticulum and the INM, and its substrates include Deg1-degron containing proteins, Ndc kinetochore mutant protein, and INM protein Asi. Nuclear E3 ligase San targets misfolded cytoplasmic and nuclear proteins for proteasomal degradation. Upon ubiquitin proteasome system overload, misfolded nuclear and cytoplasmic proteins can be reversibly sequestered into intranuclear quality compartment (INQ) by the sequestrase Btn. Upon disaggregation, misfolded proteins can be directed to refolding or degradation
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