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The body’s ability to adapt to changing conditions and shifting physiologic demands is essential to its survival. To ensure cellular performance and the health of the entire organism, each cell must be able to dispose of damaged or unnecessary proteins.



Now, a study from the Blavatnik Institute at Harvard Medical School (HMS) shows that intense exercise, fasting, and an array of hormones can activate cells’ built-in protein-disposal systems and enhance their ability to purge defective, toxic, or unneeded proteins.



The findings, published Feb. 19 in PNAS, reveal a previously unknown mechanism that is triggered by fluctuations in hormone levels, which signal changes in physiologic conditions.



“Our findings show that the body has a built-in mechanism for cranking up the molecular machinery responsible for waste-protein removal that is so critical for the cells’ ability to adapt to new conditions,” said Alfred Goldberg, senior author on the study and professor of cell biology at the Blavatnik Institute.



Cellular housecleaning in disease and health



Malfunctions in the cells’ protein-disposal machinery can lead to the accumulation of misfolded proteins, which clog up the cell, interfere with its functions, and, over time, precipitate the development of diseases, including neurodegenerative conditions such as amyotrophic lateral sclerosis and Alzheimer’s.



The best-studied biochemical system used by cells to remove junk proteins is the ubiquitin-proteasome pathway. It involves tagging defective or unneeded proteins with ubiquitin molecules — a process known as the “kiss of death” — marking them for destruction by the cell’s protein-disposal unit, known as 26S proteasome.



Past research by Goldberg’s lab has shown that this machinery can be activated by pharmacological agents that boost the levels of a molecule known as cAMP, the chemical trigger that initiates the cascade leading to protein degradation inside cells, which in turn switches on the enzyme protein kinase A. The lab’s previous research found that cAMP-stimulating drugs enhanced the destruction of defective or toxic proteins, particularly mutant proteins that can lead to neurodegenerative conditions.



The new findings, however, reveal that shifts in physiological states and corresponding changes in hormones can regulate this quality-control process independent of drugs. Goldberg’s lab previously focused on reining in overactive protein breakdown — excessive protein removal that can cause muscle wasting in cancer patients or give rise to several types of muscle atrophy. In fact, a proteasome inhibitor drug Goldberg and his team developed to tamp down protein-disposal activity has been widely used to treat multiple myeloma, a common blood cancer marked by abnormal protein accumulation and overworked proteasomes.



The team’s latest work, by contrast, is focused on developing therapies that do just the opposite — invigorate the cell’s protein-disposal machinery when it is too sluggish. These newest findings open the door, at least conceptually, to precisely such treatments.



“We believe our findings set the stage for the development of therapies that harness the cells’ natural ability to dispose of proteins and thus enhance the removal of toxic proteins that cause disease,” said study’s lead investigator, Jordan VerPlank, a postdoctoral research fellow in cell biology at the Blavatnik Institute. Such treatments may not necessarily involve the design of new molecules, but instead stimulate the cell’s built-in capacity for quality control.





“This is truly a new way of looking at whether we can turn up the cellular vacuum cleaner,” Goldberg said. “We thought this would require the development of new types of molecules, but we hadn’t truly appreciated that our cells continually activate this process.