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A systematic analysis of nuclear heat-shock protein 90 identifies a metazoan-specific regulatory module

ABSTRACT: Molecular chaperones such as heat-shock proteins (HSPs) help in protein folding and complex assembly processes. Their role in cytosol has been very well elucidated. Chaperones are also present in the nucleus, a compartment where proteins enter after being fully folded in the cytosol, raising an important question about chaperones function in this compartment. We have performed a systematic analysis of nuclear heat- shock protein 90 to identify regulatory functions of this chaperone in the nucleus. Combining physical and genetic interactomes with a cancer co-expression screen allowed us to define 'core functional interactors' of nuclear HSP90 consisting of five proteins. Using transcriptional studies we identified Host Cell Factor C1 (HCFC1) as a metazoan-specific transcriptional regulator that depends on HSP90 for its stability in the nucleus. We found that HSP90 is required for optimal activity of HCFC1 in transcription. Thus our study provides the first global insight into the function of nuclear HSP90.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE126151 | GEO | 2019/11/08

REPOSITORIES: GEO

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Project description:Proctor2005 - Actions of chaperones and their role in ageing This model is described in the article: Modelling the actions of chaperones and their role in ageing. Proctor CJ, Soti C, Boys RJ, Gillespie CS, Shanley DP, Wilkinson DJ, Kirkwood TB. Mech. Ageing Dev. 2005 Jan; 126(1): 119-131 Abstract: Many molecular chaperones are also known as heat shock proteins because they are synthesised in increased amounts after brief exposure of cells to elevated temperatures. They have many cellular functions and are involved in the folding of nascent proteins, the re-folding of denatured proteins, the prevention of protein aggregation, and assisting the targeting of proteins for degradation by the proteasome and lysosomes. They also have a role in apoptosis and are involved in modulating signals for immune and inflammatory responses. Stress-induced transcription of heat shock proteins requires the activation of heat shock factor (HSF). Under normal conditions, HSF is bound to heat shock proteins resulting in feedback repression. During stress, cellular proteins undergo denaturation and sequester heat shock proteins bound to HSF, which is then able to become transcriptionally active. The induction of heat shock proteins is impaired with age and there is also a decline in chaperone function. Aberrant/damaged proteins accumulate with age and are implicated in several important age-related conditions (e.g. Alzheimer's disease, Parkinson's disease, and cataract). Therefore, the balance between damaged proteins and available free chaperones may be greatly disturbed during ageing. We have developed a mathematical model to describe the heat shock system. The aim of the model is two-fold: to explore the heat shock system and its implications in ageing; and to demonstrate how to build a model of a biological system using our simulation system (biology of ageing e-science integration and simulation (BASIS)). This model is hosted on BioModels Database and identified by: BIOMD0000000091. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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A systematic analysis of nuclear heat-shock protein 90 identifies a metazoan-specific regulatory module

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