Sumedha B S, Bangalore University
What is Ubiquitin?
Ubiquitin is a small 76-amino acid protein found in eukaryotic cells. They are be found either freely or covalently bound to membrane proteins. It is one of the highly conserved proteins. This means its amino acid sequence is similar-from yeast to animals. It has two functional sites: the C-terminus is the site with which ubiquitin binds to acceptor proteins. A second critical residue is Lys-48 which serves as an acceptor site for ubiquitination.
What is Ubiquitination?
Ubiquitination (covalent addition of ubiquitin) like phosphorylation, plays a major role in a wide variety of regulatory mechanisms like cell cycle regulation, DNA repair, and stress response. Phosphorylation of proteins is used to change the function but ubiquitination serves as a marker that targets a protein for degradation. But, not all ubiquitinated proteins are selectively degraded.
Depending on the number of ubiquitin groups, it binds to proteins in multiple configurations. Proteins linked with a single ubiquitin include actin of insect muscle,platelet-derived growth factor receptor, and growth hormone receptor.
Role in Stress Response:
When heat, toxins, UV light, or other damaging factors come in contact with cells, it leads to cell stress. When faced with such environmental stress, eukaryotic cells initiate adaptive and reversible responses by halting cellular processes. Cells preserve cytoplasmic mRNAs in structures called“stress granules”. Also, many cellular proteins are modified by Ubiquitination. Ubiquitination is required for the degradation of misfolded or damaged proteins. This was presumed to mark the degradation of stress-damaged proteins. The mechanism of how the ubiquitinome reshapes in response to stress was not evident.
Stress granules are composed of RNA and protein. They assemble in eukaryotic cells in response to a variety of stressors. These dynamic condensates are normally disassembled when stress is removed. Though the stress granule composition and assembly are well studied, not much is known about the mechanisms responsible for its disassembly process. Persistent stress granules are degraded through autophagy, and short-lived granules undergo disassembly which is independent of autophagy.
Incorrect disassembly has been observed in some diseases including frontotemporal dementia, amyotrophic lateral sclerosis, and multisystem proteinopathy.
Recent Update:
Scientists at St. Jude Children’s Research Hospital, USA were observing the processes that enable cells in adapting to environmental stress, which can be associated with neurodegenerative diseases. They found something which was never observed before.
They used cultured human cells and found that stress granule disassembly was dependent on the type of stress. In the case of heat shock, disassembly required ubiquitination of G3BP1. This is a central protein inside the stress granule protein-RNA network.
The ubiquitinated G3BP1 interacted with endoplasmic reticulum–protein (FAF2), which triggered the ubiquitin-dependent segregate. So, targeting G3BP1 weakened the stress granule interacting network, and this resulted in granule disassembly.
When ubiquitination of G3BP1 was blocked, the stress granules formed normally but did not disassemble when the stress was removed. They also found several other important protein factors which interact with G3BP1 during the disassembly of stress granule through ubiquitination.
Scientists in addition to revealing these key pathways, identified about 10,000 modification sites on many proteins using the proteomic screen. This was used to create a resource for future studies. It can be mined to study how a specific protein or pathway is affected by ubiquitination in different types of stress.
Conclusion:
Research has shown that rather than indicating the degradation of stress-damaged proteins, ubiquitination helps to break down stress granules and restart normal cellular processes once the stress is removed. Cells generate unique types of ubiquitination as an effect of different kinds of stressors.
Thus, Ubiquitination is not required for the shutdown of cellular processes or stress granule formation but is needed after the stress is removed, for stress granule disassembly and to resume the cellular activities.
Also read: Phenotypic Imaging of Nephroblastoma Cancer cells
References:
- Maxwell, Brian Andrew, et al. “Ubiquitination is essential for recovery of cellular activities following heat shock.” bioRxiv (2021)doi: https://doi.org/10.1101/2021.04.22.440934
- Gwon, Youngdae, et al. “Ubiquitination of G3BP1 mediates stress granule disassembly in a stress-specific manner.” bioRxiv (2021). https://www.biorxiv.org/content/10.1101/2021.04.22.440930v1
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