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Housekeeping secrets of our cells are uncovered by the MRC LMB




Inside our cells, natural ‘housekeeping’ processes are going on every day.

Proteins required for basic life processes carry out this work across all cell types in the body.

Ramanujan Hegde at the MRC Laboratory of Molecular Biology. Picture: MRC LMB (22725163)
Ramanujan Hegde at the MRC Laboratory of Molecular Biology. Picture: MRC LMB (22725163)

But they require regulation. Like a parent endlessly clearing up after teenagers to prevent too much mess accumulating, our cells tightly control levels of this activity to maintain smooth operation.

The most common way of achieving this is by turning on or off genes in response to the need for the housekeeping protein products they create.

This is accomplished via feedback control of transcription – the first step in the process of gene expression, by which information from a gene is used to create a functional product like a protein.

A second method is to degrade messenger RNA (mRNA), which acts as an intermediate carrying instructions in the process of turning a gene into a protein. By stopping these messages, less protein is made.

It was almost 40 years ago that researchers noticed that cells monitor the amount of a group of housekeeping proteins called tubulins and adjust levels of tubulin mRNAs accordingly.

This is called autoregulation, but no factors in the feedback process have previously been identified – until now.

In the Cell Biology Division of the MRC Laboratory of Molecular Biology, Manu Hegde’s lab has discovered a protein used by cells to find unnecessary mRNA and trigger its destruction.

This is significant not just for our understanding of cellular processes, but also in the fight against disease.

Translating ribosomes with the emerging protein acting as a beacon. Image: MRC Laboratory of Molecular Biology (22725091)
Translating ribosomes with the emerging protein acting as a beacon. Image: MRC Laboratory of Molecular Biology (22725091)

Tubulins are key to the structure and function of neurons, and mutations in tubulin genes cause various neurodevelopmental diseases. Drugs used to treat gout and certain cancer types also target tubulin.

This means that the discovery of a factor regulating tubulin could help lead to new therapeutics for such diseases.

Zhewang Lin in Manu’s lab searched for factors that selectively engage our cells’ protein-making factories – ribosomes – when producing tubulin. He discovered a factor called TTC5 that binds only ribosomes actively making tubulin.

Working with Vish Chandrasekaran, in Venki Ramakrishnan’s group within the LMB’s Structural Studies Division, the structure of TTC5 when bound to a tubulin-producing ribosome was then determined.

They found a groove, within which the beginning of tubulin binds as it emerges from the ribosome – like an item being captured as it comes off a factory production line.

Zhewang then made mutations in TTC5, which made them unable to regulate tubulin production rates when excess was present. The factory, in other words, was allowed to go into overdrive.

The work indicated how TTC5 uses the emerging protein as a beacon to find tubulin mRNAs for degradation.

Ivana Gasic in Tim Mitchison’s lab at Harvard worked with Zhewang to show that if a working TTC5 is not present, meaning a cell cannot fine-tune its tubulin content, then the alignment and segregation of chromosomes is more prone to errors. They believe this is because tubulin plays a critical role in cell division.

It joins together to form microtubules, which control this key cellular event, along with cell movement and cell shape. Precise control of levels of tubulin is therefore vital.

Further experiments by Zhewang showed that TTC5 is not always available. It is normally sequestered – hidden – by an inhibitor, which has yet to be identified. It releases TTC5 only under conditions when cells detect too much free tubulin.

TTC5 uses the emerging protein as a beacon to find tubulin mRNAs for degradation. Image: MRC Laboratory of Molecular Biology (22725093)
TTC5 uses the emerging protein as a beacon to find tubulin mRNAs for degradation. Image: MRC Laboratory of Molecular Biology (22725093)

The researchers now hope to find this inhibitor and understand how it controls this process of sequestering and releasing TTC5.

Manu’s lab is also working to identify the machinery responsible for degrading mRNA when requested.

But the mechanism of the nascent protein acting like a beacon to find the tubulin mRNA is important.

Manu told the Cambridge Independent: “Our discovery of a central component of the ‘thermostat’ that regulates the production rate of tubulins allows us to begin understanding how such control systems operate inside the cell. Similar mechanisms are probably used to maintain other important proteins at optimal levels to keep cells healthy.”

This work was funded by the MRC, the US National Institutes of Health, the Human Frontier Science Program, the Damon Runyon Cancer Research Foundation, Harvard Medical School, the Vallee Scholars Program, the Wellcome Trust, the Agouron Institute, and the Louis-Jeantet Foundation.

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