June 14, 2023; Unhurry Expert Research Team
In This Article
The understanding of proteins linked to neurodegenerative illnesses has increased among cell biologists. The results may pave the way for novel therapeutic strategies for conditions like Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), among others.
‘Stress granules’ are clumps of RNAs and proteins that form when cells are stressed by things like heat, toxins, and viruses. Researchers at the Tokyo University of Technology have learned important things about these clumps of RNAs and proteins.
The medical community is very interested in learning how stress granules arise and how they might be eliminated because they are associated with several neurodegenerative illnesses.
The study was published in the Journal of Cell Science.
Role of two enzymes in disassembling stress granules
Two enzymes play a significant role in the breakdown of stress granules, according to the study.
These two enzymes, designated USP5 and USP13, are part of a class of almost 100 deubiquitylases that are known to exist. It is believed that these enzymes function by severing ubiquitin chains within stress granules.
The team, which consisted of Masayuki Komada, Toshiaki Fukushima, and Shunsuke Matsumoto from the Tokyo Institute of Technology (Tokyo Tech), spent more than five years working on the project. In an interview for the journal’s First-Person series, first author Xuan Xie, a PhD candidate at the laboratory directed by Komada, explained how they arrived at their “eureka” moment.
The researchers first proved that USP5 and USP13 are mostly drawn to heat-induced stress granules.
“We found that heat-induced stress granules contain ubiquitin chains, much more so than in stress granules induced by other stressors,” explains Fukushima. “This implied that ubiquitin chains may recruit USP5 and USP13 to stress granules.”
Importantly, the heat-induced stress granules served as an excellent model for subsequent research because ubiquitin chains are frequently seen in stress granules in neurodegenerative illnesses.
Effect on disassembly of stress granules
The scientists then contrasted the effects of the two enzymes on heat-shocked cells. The cells were heated to 44°C for one hour, then cooled to 37°C for another hour. The scientists discovered that the breakdown of stress granules was postponed in cells missing USP5 and USP13 throughout the recovery period.
In particular, the percentage of cells with stress granules decreased to 14% in cells expressing USP5 and USP13, but this number was 60% or more in cells lacking the two enzymes.
According to the results, USP5 and USP13 are essential for the breakdown of stress granules.
The researchers suggest that USP5 hydrolyzes or “cuts” unanchored ubiquitin chains, whereas USP13 cuts protein-conjugated ubiquitin chains, however, the precise mechanisms are still unknown.
“We concluded that both reactions are required for the efficient destabilization of stress granules,” says Fukushima.
The research may result in the creation of “artificial deubiquitinating enzymes,” which could have a significant effect on the development of new medicinal therapies.
According to Fukushima, it should be possible to create such novel enzymes that “possess high activity and show specific localization to stress granules” in five years.
 Ubiquitin chains: Chains of small regulatory proteins called ubiquitin that are found everywhere in eukaryotic cells.
 Protein-conjugated: Refers to the way that some ubiquitin chains are bound to proteins, as opposed to being unanchored, within the stress granules. One of the next goals of the team is to identify these target proteins.
Materials provided by Tokyo Institute of Technology. Note: Content may be edited for style and length.
Xuan Xie, Shunsuke Matsumoto, Akinori Endo, Toshiaki Fukushima, Hiroyuki Kawahara, Yasushi Saeki, Masayuki Komada. Deubiquitylases USP5 and USP13 are recruited to and regulate heat-induced stress granules through their deubiquitylating activities. Journal of Cell Science, 2018; 131 (8): jcs210856 DOI: 10.1242/jcs.210856
Tokyo Institute of Technology. “Goodbye ‘stress granules’: Study expands possibilities for treating neurological diseases.” ScienceDaily. ScienceDaily, 31 May 2018. <www.sciencedaily.com/releases/2018/05/180531084437.htm>.
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