Protein-folding Chaperones Have Both Positive and Negative Roles To Play in Cystic Fibrosis
New research has found that proteins involved in ensuring that other proteins are in their proper shapes may have a role to play in mitigating the effects of cystic fibrosis (CF). People with CF lack a functional copy of the CFTR gene, and the most common variant of the gene found in people with CF is designated ΔF508-CFTR. In ΔF508-CFTR, the absence of a single amino acid interferes with proper folding of the CFTR protein, not only interfering directly with its function as a channel that allows chloride ions to pass through the cell membrane, but also destabilizing the protein and causing it to be a target for degradation. The destruction of the ΔF508-CFTR protein is due in part to the activities of a group of different proteins collectively known as “chaperones,” which help ensure that other proteins are properly folded through a variety of mechanisms. For example, some chaperones assist in the initial folding of a protein, as it is being synthesized by the cell; others identify proteins that have adopted improper shapes, such as ΔF508-CFTR, and target them for degradation; and, in some cases, chaperones may be able to refold misfolded proteins into a functional state.
In new research, using cells from both mice and humans, scientists have found that the chaperones Hsc70 and Hsp90 have a limited capacity to nudge ΔF508-CFTR closer to the properly folded shape of normal CFTR protein, allowing a modest amount of chloride to flow through the channel. The researchers found that selective, chemical inhibition of Hsc70 caused the amount of ΔF508-CFTR in the cell membrane to increase, indicating that this chaperone contributes to the destruction of the misfolded channel. However, this approach further showed that despite there being more of the protein in the membrane, the ability of chloride to move through the membrane either did not rise or diminished slightly depending on the type of cell used for the experiment: this indicates that Hsc70 also has the capacity to help ΔF508-CFTR adopt a conformation closer to normal CFTR protein. In other words, the higher levels of protein in the membrane are offset by the fact that the proteins do not work as well, which is why net chloride transmission stays the same or diminishes. Selective inhibition of Hsp90 had little impact on the amount of ΔF508-CFTR in the membrane, but significantly reduced the ability of the channels present to transmit chloride, indicating that Hsp90 can help ΔF508-CFTR adopt a more functional conformation—presumably closer to that of normal CFTR protein—without promoting its degradation. Inhibiting both chaperones had an even more profound effect, reducing chloride transmission by more than half. Importantly, addition of Hsc70 and Hsp90—along with specific protein partners called co-chaperones—increased the ability of ΔF508-CFTR to permit passage of chloride through the membrane. Experiments further suggested that when working with one co-chaperone, Hsc70 may promote ΔF508-CFTR destruction, while with another co-chaperone Hsc70 might promote improved channel function.
These discoveries suggest that manipulating the activity of chaperones is worth exploring as a potential means of treating CF and perhaps other diseases caused by destabilized cell surface proteins.