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Nov 15

ALS protein plays important role in stress response

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A new study by Packard scientist Jiou Wang reveals how the ALS-linked protein ubiquilin 2 helps to regulate RNA and protein balance when the cell is stressed.

Over the past few years, an increasing number of studies in ALS have begun to point to abnormalities in the cellular regulation of RNA and protein homeostasis as sitting at the heart of the disease. A new study published in the journal PNAS by Packard scientist Jiou Wang reveals how the ALS-linked protein ubiquilin 2 helps to regulate RNA and protein balance when the cell is stressed.

Stress is inevitable. Every living thing, from the simplest single-cell organism to humans, need to find ways to adapt to a stressful environment. At the cellular level, stress can cause proteins to misfold, which interferes with their ability to do their normal jobs. It can also stall the translation of RNA to protein. One way that cells cope is by creating stress granules, clumps of protein and RNA that sequester molecules that might otherwise harm the cell. Normally, these granules dissolve when the stress passes. In ALS patients, however, the dynamics of these granules often becomes abnormal. What results is a buildup of toxic clumps that ultimately kills motor neurons.

In 2011, a team of researchers in Chicago showed that mutations in the UBQLN2 gene caused a rare form of ALS with dementia, although scientists couldn’t figure out exactly how the mutation led to disease. Wang and colleagues worked to identify proteins that interacted with UBQLN2, which they hoped would provide them with clues about the protein’s function. Their search identified 181 possibilities, which they grouped into four different categories.

As they analyzed the results, they realized that members of three of the four categories also included components of stress granules, which indicates that UBQLN2 interacts with stress granule proteins even when the cell isn’t stressed. Surprisingly, UBQLN2 itself is a component of stress granules, which the authors discovered when they used an improved cell straining method. If the cellular stress is prolonged, however, the association begins to break down. UBQLN2 appeared to dissociate from the stress granule, showing a time-dependent and dynamic regulation.

The UBQLN2 protein is made up of two major domains connected by a linker region. Computer analysis revealed that this linker region contained segments that would allow it to associate both with itself and with other proteins. The researchers engineered cells that would express just this linker region, which they subsequently located in stress granules. This indicated that the linker region was enough to direct UBQLN2 to the stress granules.

Contrary to what the researchers thought, increasing the production of UBQLN2 did not cause a rise in stress granule production. Instead, UBQLN2 overexpression led to a suppression of stress granule formation. The reverse was also true: The depletion of UBQLN2 resulted in a nearly twofold increase in the percentage of cells with large stress granules as early as 30 minutes after stressor onset. Among these cells with depleted UBQLN2, those with relatively higher levels of the protein had lower levels of large stress granules. Taken together, these results show that UBQLN2 negatively regulates stress granule size.

A further set of experiments revealed that UBQLN2 also interacts with an ALS-linked protein called FUS and can influence how FUS binds to RNA. UBQLN2 also affects the dynamics of how mutant FUS interacts with RNA, although mutant UBQLN2 does not. Integral to the formation of stress granules is a process called liquid-liquid phase separation, in which proteins like FUS shift from a diffuse state into granules, which could further grow into large aggregates. The action of UBQLN2 inhibits the formation of large FUS-RNA complexes that are key to the liquid-to-solid transition of FUS.

All of these findings together indicate that UBQLN2 helps to prevent the formation of stress granules, giving it a central role at the intersection of the malfunctioning protein and RNA regulation that underlies ALS.

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