Sending "Lost" Proteins Back Home

Picture your body as a busy city, and proteins as workers doing specific jobs. Now, imagine if those workers start showing up at the wrong offices — lifeguards in the desert, gardeners at the bank, and plumbers in the playground. Chaos would ensue. This is what happens in your own cells when proteins end up in the wrong place, and this mix-up has been shown to cause serious diseases, including Alzheimer's and cancer. Protein localization, as scientists call it, is crucial in order to keep your cellular world and body healthy.

But what if there was a way to restore misplaced proteins back to their original locations? In a groundbreaking development at the intersection of biology and chemistry, a team of scientists from Professor Stuart Schreiber’s laboratory at Harvard University have unveiled a newly engineered molecule, aptly named “NICE-01” (nuclear import and control of expression compound 1), that has the ability to shuttle specific proteins within a cell back to their proper locations. 

Broadly speaking, human cells can be divided into two main compartments: the nucleus and the cytoplasm. These compartments are physically separated by a double-layered membrane, so if a nuclear protein is misplaced in the cytoplasm, or vice-versa, it is challenging for the cell to naturally transport that protein back to its correct place. In fact, the translocation of proteins from one compartment to another is the defining event of several human diseases. For example, the mislocalization of the nuclear protein TDP-43 in the cytoplasm is a driving cause of amyotrophic lateral sclerosis (ALS), and the misplacement of the huntingtin protein in the nucleus causes clumping inside brain cells, resulting in Hunginton’s disease.

The most common type of acute myeloid leukemia is caused when the nuclear protein called nucleophosmin, or NPM1, becomes localized in the cytoplasm, preventing it from performing its normal function of inhibiting cell growth and division in the nucleus. Schreiber’s team sought to determine whether NICE-01 could be harnessed to move NPM1 back to the nucleus in leukemia cells. In fact, just 10 µM of NICE-01 was sufficient. NICE-01 works by acting as a molecular glue, using specific covalent interactions to cause cytoplasmic proteins such as NPM1 to stick to nuclear proteins, such as those belonging to the BET bromodomain family. Because BET proteins normally localize in the nucleus, NPM1 is carried along with it back to its nuclear residence. This targeted relocalization restores the proper functioning of NPM1, consequently addressing disrupted cellular processes associated with acute myeloid leukemia. This approach presents a promising avenue for the development of targeted therapies for other diseases driven by protein mislocalization.

Perhaps even more exciting, Schreiber’s team discovered that NICE-01 could be harnessed to control which proteins a cell produces. This can have several therapeutic implications in the field of cancer treatment. Many cancers are driven by the lack of so-called “tumor suppressor” proteins, which normally work to dampen cell growth and division. By restoring the production of tumor suppressor proteins in these cancers, it becomes possible to reinstate a natural check on uncontrolled cell proliferation.

This is possible due to the presence of transcription factors, which are large molecules that help induce the production of specific proteins. Transcription factors initiate protein production in the nucleus, but most of the time, they are not active and are instead located in the cytoplasm. Therefore, to induce the production of a specific protein, researchers can harness NICE-01 to bind to the corresponding transcription factor and carry it to the nucleus. Think of it like bringing a “start” button into the nucleus. Each transcription factor is a start button for the production of a specific protein, and NICE-01 can be programmed to carry any specific start button into the nucleus, where it can perform its function. This approach harnesses the intricacies of protein regulation, offering a nuanced and powerful strategy that complements the transformative potential of gene editing technologies in the pursuit of more effective cancer therapies.

By directing proteins to specific locations within cells, researchers can target the root causes of diseases with unprecedented accuracy. Schreiber remains optimistic about the future discoveries that this technology will bring, concluding, “We anticipate that future bifunctional relocalizing molecules will have important applications in scientific discovery and human therapeutics.” As the scientific community marvels at this groundbreaking achievement, NICE-01 offers a glimpse into a future where diseases are not just treated but precisely and effectively targeted at the molecular level.

Original Article:  https://doi.org/10.1021/jacs.3c06179