Many Native American tribes speak of shape-shifting, when a human transforms into a spirit or animal. In many cases, this is intended for destructive purposes. Scientists have developed a similar concept known as frameshifting (or more properly programmed ribosomal frameshifting). Frameshifting refers to a quick alteration that can occur in a gene’s operating instructions in order to transform protein content, function, and ability to survive. Now, a new study conducted by researchers at University of Maryland reveals how our genes frameshift for positive purposes, such as modulating our body’s immune response.
Ribosomes: The Protein Factory In Every Living Cell
Proteins are made from amino acids, which are themselves formed from triads of nucleotides called codons, which essentially spell out the protein they intend to become. Within each cell, a ribosome’s job is to gather amino acids and assemble them into protein chains. Yet, a ribosome can only perform this role with the help of RNA (ribonucleic acid). First, transfer RNA reads the instructions of each codon, and second, messenger RNA delivers the matching amino acids to the ribosome for assembly. To build proteins properly, then, all three nucleotides in each codon must be read correctly; yet, sometimes the messenger RNA jumps forward or back by one or two places along the codon triad — that is, a signal within the RNA shifts the reading frame and jumbles the text. When this happens, the ribosome has effectively been reprogrammed, resulting in that ribosome assembling either new proteins or nonsense proteins.
Frameshift signals are common in some viruses, which use them to cram multiple commands onto a single RNA strand thereby rendering them ineffective or destructive. Yet, Dr, Jonathan Dinman, senior author and professor of cell biology and molecular genetics at UMD, has long suspected human cells also have frameshift signals that are useful.
For his new study, Dinman and colleagues studied CCR5, a gene on the surface of humans' white blood cells. CCR5 is important to the immune system, but some forms of HIV use it to enter healthy cells. Examining it more closely, Dinman and his team found a molecular pattern that works as a frameshift signal in CCR5. Through experimentation, they discovered the signal prompted the ribosome to frameshift 10 to 15 percent of the time and next, they confirmed frameshifting was happening within CCR5 using mass spectroscopy. "It wasn't until the past decade that computers were fast and powerful enough to find these signals,” said Dinman, who has been studying ribosomal frameshifting since the 1990s. After more investigation, they saw how a small specialized piece of RNA, called microRNA-1224, attaches itself to CCR5's messenger RNA at the frameshift site.
This appeared to be the key step, then. By bracing the messenger RNA, microRNA makes the messenger RNA less flexible, and in turn, this causes the ribosome to slip by one or two spaces more often. MicroRNA-1224 appeared to be regulating the process.
"The biggest question in this field has been, what regulates frameshifting? And that's essentially what microRNA-1224 is doing," Dinman said. "Then the question becomes, what are the consequences?"
In the case of CCR5, the frameshift changes the codons into nonsense RNA. Next, other components of the cell step in to destroy the messenger RNA and its associated proteins. This might seem like a bad thing, but Dinman believes that by killing the RNA and its array of immune system proteins, frameshifting acts like a dimmer switch, lowering the body’s immune response to a safe level. (Immune response, remember, is what causes fevers and inflammation.) Considering his team’s discovery, Dinman said the work may lead to better treatments for AIDS, allergies, and rejection of transplanted organs.
Source: Belew AT, Meskauskas A, Musalgaonkar S, et al. Ribosomal frameshifting in the CCR5 mRNA is regulated by miRNAs and the NMD pathway. Nature. 2014.