In the cell, waste management has been thought to be dominated by the ubiquitin–proteasome system. Now it appears that an alternative system has a piece of the action. According to University of Gothenburg researchers, this system passes waste through the nuclear membrane. The researchers say that the system can help remove waste that can build up in the nucleus if the ubiquitin–proteasome system is overwhelmed or disabled.

The alternative system relies on a mechanism called nuclear envelope budding (NEB), which is distinct from the transport mechanism associated with the nuclear pore complex. NEB is a “ubiquitous eukaryotic phenomenon” that contributes to protein quality control, reported the Gothenburg team, which was led by Johanna L. Höög, PhD, associate professor of chemistry and molecular biology. Moreover, the team found that NEB intensifies when cells are exposed to various forms of cellular stress. According to the team, disabling NEB could be an effective way to treat Alzheimer’s disease and cancer.

The team’s findings recently appeared in the journal PNAS, in an article titled, “Nuclear envelope budding is a response to cellular stress.” The article describes how Höög and colleagues used quantitative electron microscopy (EM) and tomography to demonstrate that NEB is evolutionarily conserved from early protists to human cells. The article also reports that NEB events occur more frequently in cells that are stressed, or in cells in which the proteasome is inhibited.

“We present here three different lines of evidence that NEB is a widely conserved, physiologically normal cellular process that increases in frequency due to cellular stress and is specifically activated by an increase in protein aggregation,” wrote the article’s authors. “First, we observed that five distinct stress conditions—heat shock, hydrogen peroxide, arsenite, proteasome inhibition, and azetidine-2-carboxylic acid (AZC) treatment—all led to an increase in the frequency of NEB, with the AZC treatment most prominently activating the NEB pathway among all stressors. Second, immuno-EM revealed the presence of ubiquitin and Hsp104, a protein disaggregase, in the cargo of the buds, which supports our hypothesis that this pathway is involved in protein degradation. Third, NEB events were detected in every species examined, from T. brucei to human cell line HMC-1.”

Inside a cell, new proteins are continually formed, while other proteins are broken down to their constituent parts and recycled. This is important for the cell’s health since, just like the buildup of waste in any environment, damaged proteins can become poisonous. “It is perhaps most important that the damaged proteins are separated from the genome, where they can cause mutations that in turn can cause more damaged proteins,” Höög observed.

Badly functioning waste management in the cell can create a downward spiral where waste eventually kills the cell. This sometimes occurs in the brain with Alzheimer’s disease and in some other forms of dementia.

In the current study, the researchers show that the NEB pathway can remove cellular waste that otherwise could damage the cell’s genome. “This insight in the cell’s normal function,” Höög noted, “can be important for treatment of dementia.”

Höög and colleagues also emphasized that the discovery of the NEB pathway could lead to new, more effective treatments for cancer, particularly since the cell’s waste management system already is a focus of attack for cancer treatments.

“Cancer cells produce more waste than healthy cells,” Höög explained. “This is used by some chemotherapies that stop normal cell waste management to result in the faster death of the cancer cells than our normal cells, forcing the cancer into remission.”

When the researchers treated the cells with a chemical that stops waste processing and today is used for cancer treatments, the transport of waste through the cell nucleus membrane increased.

“You could say that we sealed all the openings in the cell’s treatment plant, known as proteasomes,” Höög pointed out. “This caused the cell to compensate and remove the incorrectly folded proteins through this transport pathway instead. We now hope to receive more research funding to study the molecular mechanisms behind this cellular waste transport and look more closely at the phenomenon in cancer cells.”

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