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Massachusetts General Hospital (MGH) investigators have discovered the mechanism by which cells sense dysfunction of the proteasome—a cellular component that degrades unneeded or defective proteins—and respond in a previously undescribed manner, by editing the amino acid sequence of a key sensing protein. Proteasome dysfunction can lead to the type of buildup of aberrant proteins that characterizes neurodegenerative disorders such as Alzheimer's disease and is also seen in normal aging. The report is being published in the journal Cell.
The proteasome is comprised of around 20 proteins that form a structure in which unneeded cellular proteins are disposed of in a highly regulated manner. Healthy cells respond to protease dysfunction by increasing production of its component proteins. Two years ago investigators Gary Ruvkun, Ph.D. senior author of the Cell paper, and lead author Nicolas Lehrbach, Ph.D. - both of the MGH Department of Molecular Biology - identified a cascade of sensing and signaling proteins, including the transcription factor SKN-1A, that allows cells in the C. elegans roundworm to detect and respond to proteasome dysfunction.
Cell - Paper - Peter - Breen - Ruvkun
The Cell paper, co-authored by Peter Breen of Ruvkun's lab, describes how SKN-1A and its mammalian counterpart Nrf1 are modified by the addition of a sugar molecule called a glycan, a modification that is common on proteins secreted from cells but rare on DNA-binding regulatory proteins. Under normal circumstances, SKN-1A/Nrf1 is efficiently degraded by the proteasome, making that protein a natural monitor of proteasomal function. If proteasomal capacity is exceeded, for example by an excess aggregation of proteins, SKN-1A/Nrf1 is not completely degraded and binds to the DNA adjacent to proteasomal genes, inducing the production of additional proteasomes until the protein is again sufficiently degraded.
In their 2016 paper, Lehrbach and Ruvkun proved that activation of SKN-1A/Nrf1 requires enzymatic clipping of the protein as well as the addition and subsequent...
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