Cdc48 regulates intranuclear quality control sequestration of the Hsh155 splicing factor

Mathew, Veena; Kumar, Arun; Jiang, Yangyang Kate; West, K.A.; Tam, Annie; Stirling, Peter C.

doi:10.1101/2020.06.16.152934

Cited by 3 publications

References 33 publications

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Phenotypic Heterogeneity in the DNA Replication Stress Response Revealed by Quantitative Protein Dynamics Measurements

Loll-Krippleber

Torres

et al. 2022

Preprint

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Cells respond to environmental stressors by activating programs that result in protein abundance and localization changes. The DNA damage and DNA replication stress responses have been heavily studied and provide exemplars of the roles of protein localization and abundance regulation in proper cellular stress response. While vast amounts of data have been collected to describe the dynamics of yeast proteins in response to numerous external stresses, few have assessed and compared both protein localization kinetics and phenotypic heterogeneity in the same context, particularly during DNA replication stress. We developed a robust yet simple quantification scheme to identify and measure protein localization change events (re-localization) and applied it to the 314 yeast proteins whose subcellular distribution changes following DNA replication stress. We captured different kinetics of protein re-localization, identified proteins with localization changes that were not detected in previous analyses, and defined the extent of heterogeneity in stress-induced protein re-localization. Our imaging platforms and analysis pipeline enables efficient measurements of protein localization phenotypes for single cells over time and will guide future work in elucidating the biological parameters that govern cellular heterogeneity.

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Phenotypic Heterogeneity in the DNA Replication Stress Response Revealed by Quantitative Protein Dynamics Measurements

Loll-Krippleber

Torres

et al. 2022

Preprint

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K29-linked unanchored polyubiquitin chains disrupt ribosome biogenesis and direct ribosomal proteins to the Intranuclear Quality control compartment (INQ)

Suresh

Bonneil

Albert

et al. 2023

Preprint

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Ribosome assembly requires precise coordination between the production and assembly of ribosomal components. Mutations in ribosomal proteins that inhibit the assembly process or ribosome function are often associated with Ribosomopathies, some of which are linked to defects in proteostasis. In this study, we examine the interplay between several yeast proteostasis enzymes, including deubiquitylases (DUBs), Ubp2 and Ubp14, and E3 ligases, Ufd4 and Hul5, and we explore their roles in the regulation of the cellular levels of K29-linked unanchored polyubiquitin (polyUb) chains. Accumulating K29-linked unanchored polyUb chains associate with maturing ribosomes to disrupt their assembly, activate the Ribosome assembly stress response (RASTR), and lead to the sequestration of ribosomal proteins at the Intranuclear Quality control compartment (INQ). These findings reveal the physiological relevance of INQ and provide insights into mechanisms of cellular toxicity associated with Ribosomopathies.

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Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases

Chu,

Xie,

Payan

et al. 2023

Mol Neurodegeneration

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The AAA+ ATPase valosin containing protein (VCP) is essential for cell and organ homeostasis, especially in cells of the nervous system. As part of a large network, VCP collaborates with many cofactors to ensure proteostasis under normal, stress, and disease conditions. A large number of mutations have revealed the importance of VCP for human health. In particular, VCP facilitates the dismantling of protein aggregates and the removal of dysfunctional organelles. These are critical events to prevent malfunction of the brain and other parts of the nervous system. In line with this idea, VCP mutants are linked to the onset and progression of neurodegeneration and other diseases. The intricate molecular mechanisms that connect VCP mutations to distinct brain pathologies continue to be uncovered. Emerging evidence supports the model that VCP controls cellular functions on multiple levels and in a cell type specific fashion. Accordingly, VCP mutants derail cellular homeostasis through several mechanisms that can instigate disease. Our review focuses on the association between VCP malfunction and neurodegeneration. We discuss the latest insights in the field, emphasize open questions, and speculate on the potential of VCP as a drug target for some of the most devastating forms of neurodegeneration.

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Cdc48 regulates intranuclear quality control sequestration of the Hsh155 splicing factor

Cited by 3 publications

References 33 publications

Phenotypic Heterogeneity in the DNA Replication Stress Response Revealed by Quantitative Protein Dynamics Measurements

Phenotypic Heterogeneity in the DNA Replication Stress Response Revealed by Quantitative Protein Dynamics Measurements

K29-linked unanchored polyubiquitin chains disrupt ribosome biogenesis and direct ribosomal proteins to the Intranuclear Quality control compartment (INQ)

Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases

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