Better together: researchers discover how cells promote the collective equilibrium of proteins
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Image: Top images are produced by a confocal microscope and show the localisation of TRA2B, an RNA-binding protein that is present in cell nuclei. TRA2B binds to the multivalent mRNAs and brings them to the speckles during interstasis. These images show the change in the localisation of TRA2B. The schematic at the bottom sums up the mechanism of interstasis. On the left is a cell with dynamic speckles that allow efficient mRNA export and synthesis of condensation-prone proteins. On the right, the cell has transitioned into interstasis because these proteins have accumulated within nuclear speckles, thereby attracting the TRA2B protein that captures the multivalent mRNAs. This delays the nuclear export of multivalent mRNAs, thus decreasing further synthesis of condensation-prone proteins. Thus, interstasis could help bring the speckles back to their original state and thus restore cellular homeostasis.
The amount of any given protein in a cell has to be controlled to keep its levels within a range required for healthy functions. And this is especially important for proteins that are known to group together in liquid droplets called ‘condensates’. These proteins generally contain flexible parts that don’t have fixed 3D structures, so they can form many interactions at the same time. When these proteins accumulate, they are prone to forming aggregates.
Proteins that have similar flexible parts tend to condense together, so their equilibrium is a collective problem for the cell. “I compare accumulation of these proteins to global warming, where we’re all contributing a tiny bit too much to greenhouse gas emissions and that adds up to cause a huge problem,” explains Jernej Ule, who leads a lab at the Crick. “Similarly, small increases in many individual proteins could collectively cause a big effect on their shared condensate.”
Jernej also leads the UK Dementia Research Institute at King’s College London, and co-supervises a satellite research group at the National Institute of Chemistry in Ljubljana (NIC). He’s interested in these flexible proteins because their accumulation or aggregation can be toxic to the cell, causing conditions like neurodegenerative diseases.
Aiming to discover how the cell regulates the amounts of these types of proteins, Rupert Faraway and Neve Costello Heaven in Jernej’s team investigated so-called ‘nuclear speckles’ - condensates in the nucleus that contain diverse proteins and RNAs.
Their findings, published today in Nature, enabled them to discover a new way for cells to maintain the equilibrium of many co-condensing proteins.
Interstasis: solving a collective problem
Rupert first used a computer programme to find that many messenger molecules, called mRNAs, contain ‘red flags’ of repeated sequences. These sequences tend to encode the flexible parts of proteins.
“Interestingly, evolution introduced strong biases in the codons that promote such repetitive sequences in mRNAs, and each type of repetitive sequences encodes flexible parts of proteins with related functions,” says Rupert. One type of such sequences encodes mix-charged regions in nuclear proteins that primarily function in the regulation of gene expression. “And it’s this similarity in mRNA sequences that helps the cell regain equilibrium if too many of these proteins are gathering in nuclear speckles.”
Neve then used fluorescent tags to see what happened if mix-charged proteins gathered in this way. She explains, “When the amounts of these proteins in speckles were increased, we saw a build-up of their own mRNAs also within the speckles. And this decreased further production of these proteins, thus promoting their collective equilibrium.”
The team termed this process ‘interstasis’: how accumulation of various proteins in a condensate can decrease further production of the same proteins by capturing their own mRNAs into the same condensate. When their mRNAs are taken into the speckles, cells can’t produce more of the same protein. Neža Vadnjal, based at NIC, has worked with Neve to demonstrate that this capture into speckles depends on specific types of repetitive sequeunces within mRNAs.
Klara Kuret Hodnik and Jure Rebselj, also based at NIC, have performed in-depth computational analyses and modelling to find that interstasis enables the cell to regulate genes that are particularly ‘dosage-dependent’ – their levels have to be just right.
Does interstasis fail in neurodegeneration?
The team’s discovery has opened doors to study what happens if interstasis fails to control a build-up of these types of proteins.
“Many diseases of ageing involve the build-up of proteins that coalesce in condensates,” says Jernej. “We’re now exploring the role of interstasis in controlling the proteins that play a role in neurodegeneration, and whether a failure of interstasis could impact aggregation of these proteins.”
He concludes, “Lots of areas of biology focus on feedback loops that control a specific gene, protein or pathway. We’ve taken a step back and looked at the cell’s capacity for maintaining equilibrium of a large condensate that one can see under a light microscope, thereby co-regulating proteins that participate in many different pathways. I’m hopeful that this will inspire other researchers to explore how protein-mRNA feedback in condensates might promote homeostasis in various areas of biology.”
Image: Example images produced by a confocal microscope showing the signal of nuclear speckles, a mix-charged protein that is induced in subset of cells, and a specific mRNA that doesn’t respond to interstasis (control) or mRNA that contains repetitive sequences (multivalent mRNA). Only the multivalent mRNA is captured into nuclear speckles in the cells that express the mix-charged protein.
ONLINE LINK: https://www.nature.com/articles/s41586-025-09568-w
CONTACT PERSON: jernej.ule(at)ki.si