Sci. Aging Knowl. Environ., 30 March 2005
Mopping Up Nuclear Waste
Molecule helps dispose of damaged proteins in the cell's command center
A cell relies on molecular janitors to clear away trashed proteins, but researchers didn't know whether these cleanup crews tidied the nucleus. However, a new study identifies a housekeeping molecule that works in that structure, dispatching damaged proteins to the cell's refuse incinerator. The molecule may play a role in illnesses that involve protein buildup in the nucleus, such as Parkinson's disease (PD).
Enzymes sweep up misfolded or marred proteins that appear in the cytoplasm and adorn them with the molecule ubiquitin. The tagged proteins then get minced in the proteasome, the cellular garbage disposal (see Gray Perspective). Although the nucleus sports proteasomes, researchers haven't determined whether it houses a ubiquitin-tagging mechanism for broken-down proteins. Such a system would be particularly important for the nucleus because protein clumps there trigger diseases such as PD, says yeast biologist Daniel Gottschling of the Fred Hutchinson Cancer Research Center in Seattle, Washington. He and his colleagues decided to look for one in yeast. The fungus is a good place to search for such a protein "quality-control" mechanism because the membrane that envelops the nucleus doesn't break down during division, says Gottschling. As a result, waste disposal proteins in the cytoplasm never get a chance to deal with noxious proteins that form in the nucleus.
To finger possible nuclear cleaners, the researchers started by scanning the literature for molecules that cull proteins warped by heat. They found one called San1p that, studies suggested, might trim amounts of two nuclear proteins. The team then tested San1p's ability to eliminate faulty versions of those proteins, Sir4p and Cdc68p. Both proteins dwindled rapidly in yeast cells that made normal San1p, but not in cells that carried a nonfunctional version of the putative cleanup protein. Analysis of San1p's amino acid sequence revealed a stretch that guides the protein to the nucleus. When the researchers tampered with the sequence, yeast could no longer dispose of flawed Sir4p and Cdc68p, confirming that San1p operates in the nucleus. The team then showed that San1p affixes ubiquitin tags to its targets. Further experiments demonstrated that yeast with a broken proteasome can't discard defective Sir4p. Overall, the results suggest that San1p clears away damaged proteins in the nucleus by affixing ubiquitin, which dooms the proteins to destruction in the proteasome. Animals carry genes that make proteins similar to San1p, says Gottschling, suggesting that a comparable mechanism might cleanse the nuclei of human cells.
"This is the first case in which damaged proteins are targeted in the nucleus," says molecular cell biologist David Goldfarb of the University of Rochester in New York. What makes the results exciting is the possibility that a similar system goes awry in diseases in which proteins amass in the nucleus, he says. But researchers now need to determine whether a comparable protein functions in mammals and pin down San1p's targets, he adds. That work might reveal whether our cells can prevent the nucleus from getting trashed.
March 30, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150