The RNA Research Team at the Institute for Basic Science Identifies the Role of Proton Ions in Immune Signal Transmission
“TRIM25 Protein Removes mRNA… Less Effective Against N1-methylpsuedouridine Base”, [Photo: Provided by the Ministry of Science and ICT],
(Seoul=News1) Reporter Yoon Joo-young = A Korean research team has uncovered clues that could significantly enhance the development of ‘messenger RNA’ (mRNA) vaccines, which are emerging as a new therapeutic platform. They also discovered for the first time that proton ions act as immune signal transmitters.
‘It is expected to improve the efficacy and stability of mRNA vaccines for treating infections such as COVID-19 in the future.’
According to the Ministry of Science and ICT on the 4th, the research team led by Director Kim V. Narry at the Institute for Basic Science (IBS) has identified a group of proteins that control the delivery and degradation of mRNA vaccines within cells, revealing their mechanisms for the first time.
mRNA functions by transmitting genetic information from DNA to ribosomes within the cell cytoplasm to synthesize proteins. mRNA-based technology is anticipated to be utilized not only for addressing infectious diseases like COVID-19 but also for cancer vaccines and immune and gene therapies.
Especially with the development of ‘lipid nanoparticles’ as delivery substances within the body, mRNA technology is emerging as an innovative therapeutic platform.
However, the precise actions of how therapeutic RNA operates and is regulated have not been fully elucidated. For instance, the modified nucleotide ‘N1-methylpsuedouridine,’ a key component in the commercialization of mRNA vaccines such as COVID-19 vaccines, had an unclear underlying principle.
The IBS research team meticulously used gene-editing screening to identify intracellular factors that control mRNA.
They discovered that the ‘heparan sulfate proteoglycan’ (HSPG) molecule binds with lipid nanoparticles enveloping mRNA to promote cell entry.
They further found that the proton ion pump ‘V-type ATPase’ acidifies the interior of the endoplasmic reticulum, allowing lipid nanoparticles to acquire a positive charge, which temporarily disrupts the endoplasmic reticulum membrane. This disruption leads to the release of mRNA into the cytoplasm, where it is expressed into proteins.
Additionally, the research team discovered for the first time the role of proton ions in alerting to the intrusion of external RNA, along with inhibiting factors for RNA therapeutics.
The ‘TRIM25’ protein in the cytoplasm recognizes mRNA as an intruder and removes it. This protein is an RNA-binding protein and ligase that regulates innate responses, such as viral infection. It is activated by proton ions released when the endoplasmic reticulum membrane is disrupted.
TRIM25 targets and binds to exogenous (externally acting) RNA and rapidly degrades it alongside other enzymes and auxiliary proteins.
Furthermore, the team found that the TRIM25 protein, which binds and removes mRNA, shows significantly reduced binding to the N1-methylpsuedouridine modified base, thus failing to cleave and degrade the mRNA.
Director Kim stated, “Understanding the cell’s defense mechanisms against external intruders will not only advance RNA research but also suggest new research directions in areas like immunity and cell signaling.”
The research was published online in the world-renowned journal “Science” on the 4th.