Dataset Information

Proteome solubility changes under different proteostasis stresses

ABSTRACT: The accumulation of aberrant protein aggregates in neurodegenerative diseases is associated with a widespread failure of the protein homeostasis system. To investigate whether there is a subproteome that consistently aggregates under stress and define the broader determinants for protein aggregation at the proteome level we measured the changes in proteome solubility of a mouse neuroblastoma cell line (Neuro2a) under 6 different protein homeostasis stresses, including a Huntington’s disease model, Hsp70, Hsp90, proteasome and ER-mediated folding inhibition, and oxidative stress. By partitioning cell lysates into supernatants and pellets by centrifugation, we found that just over a one-quarter of the proteome extensively changed in solubility upon one or more stresses. Surprisingly, almost all the increases in insolubility were counteracted by increases on solubility of other proteins. Each stress directed a highly specific pattern of change, which reflected the remodelling of protein complexes involved in adaptation to perturbation, most notably stress granule proteins, which were highly enriched but responded differently across the different 2 stresses. The solubility patterns clustered into molecular functions anticipated from stress responses and metabolic pathway hotspots, and indicate a robust rewiring of protein-ligand interactions.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Xiaojing Sui

LAB HEAD: Daniel Martin Hatters

PROVIDER: PXD015573 | Pride | 2020-01-29

REPOSITORIES: Pride

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Widespread remodeling of proteome solubility in response to different protein homeostasis stresses.

Sui Xiaojing X Pires Douglas E V DEV Ormsby Angelique R AR Cox Dezerae D Nie Shuai S Vecchi Giulia G Vendruscolo Michele M Ascher David B DB Reid Gavin E GE Hatters Danny M DM

Proceedings of the National Academy of Sciences of the United States of America 20200121 5

The accumulation of protein deposits in neurodegenerative diseases has been hypothesized to depend on a metastable subproteome vulnerable to aggregation. To investigate this phenomenon and the mechanisms that regulate it, we measured the solubility of the proteome in the mouse Neuro2a cell line under six different protein homeostasis stresses: 1) Huntington's disease proteotoxicity, 2) Hsp70, 3) Hsp90, 4) proteasome, 5) endoplasmic reticulum (ER)-mediated folding inhibition, and 6) oxidative str ...[more]

PMID: 31964829

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Project description:Abstract Background The extraordinarily resistant bacterium Deinococcus radiodurans withstands harsh environmental conditions present in outer space. Deinococcus radiodurans was exposed for one year outside the International Space Station within Tanpopo orbital mission to investigate microbial survival and space travel. In addition, a ground-based simulation experiment with conditions, mirroring those from Low Earth orbit, was performed. Methods We monitored Deinococcus radiodurans cells during early stage of recovery after Low Earth orbit exposure using electron microscopy tools. Furthermore, proteomic, transcriptomic and metabolomic analyses were performed to identify molecular mechanisms responsible for the survival of Deinococcus radiodurans in Low Earth orbit. Results D. radiodurans cells exposed to low Earth orbit conditions do not exhibit any morphological damage. However, an accumulation of numerous outer-membrane associated vesicles was observed. On levels of proteins and transcripts, a multifaceted response was detected to alleviate cell stress. The UvrABC endonuclease excision repair mechanism was triggered to cope with DNA damage. Defense against reactive oxygen species is mirrored by the increased abundance of catalases and is accompanied by the increased abundance of putrescine which works as scavenging molecule. In addition, several proteins and mRNAs, responsible for regulatory and transporting functions showed increased abundances. The decrease in primary metabolites indicate alternations in the energy status, which is needed to repair damaged molecules. Conclusion Low Earth orbit induced molecular rearrangements trigger multiple components of metabolic stress response and regulatory networks in exposed microbial cells. Presented results show that the non-sporulating bacterium Deinococcus radiodurans survived long-term Low Earth orbit exposure if wavelength below 200 nm are not present, which mirrors the UV spectrum of Mars, where CO2 effectively provides a shield below 190 nm. These results should be considered in the context of planetary protection concerns and the development of new sterilization techniques for future space missions.

Dataset Information

Proteome solubility changes under different proteostasis stresses

Publications

Widespread remodeling of proteome solubility in response to different protein homeostasis stresses.

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