Can Cigarette Smoking Cause Loss of Folliculin?

Birt-Hogg-Dubé Syndrome (BHD) is caused by mutations in the gene folliculin (FLCN). It is characterised by skin bumps called fibrofolliculomas, lung cysts, collapsed lungs and an increased risk of kidney cancer. The changes taking place in the cell that lead to these symptoms are not well understood. However, there have been a few studies trying to look at how loss of FLCN can lead to lung cysts. One possibility is that loss of FLCN may lead to damage in the lung tissue which causes the formation of lung cysts. The lung cysts in BHD are not thought to affect the function of the lungs. Most people with BHD have good lung function which does not get worse over time.

Another condition that is caused by damage in the lung tissue and the formation of lung cysts is emphysema. Emphysema is a type of chronic obstructive pulmonary disease (COPD). People with COPD often have a cough and can feel breathless or have trouble breathing. It is a progressive disease meaning it gets worse over time and there is no cure. Treatments are available that can slow the progression of lung disease. The most common cause of COPD is smoking.

In people with BHD, smoking is not thought to impact lung cyst formation or lung function. However, it is not clear whether smoking and COPD affect FLCN function. A recent study aimed to look at the effect of cigarette smoking on FLCN.

First, the researchers took samples of lung tissue from people who smoked and had COPD, people who smoked but had no lung disease and non-smokers with no lung disease. They looked at the amount of FLCN protein in the samples and saw that those with COPD had less FLCN protein compared to people with no lung disease.  There was no difference in the amount of FLCN protein between people who smoked (with no lung disease) and those who didn’t. Next, the authors looked at the effect of cigarette smoke exposure on FLCN. They used a mouse model and exposed them to cigarette smoke for 6 weeks, 6 months, or to no cigarette smoke at all. The researchers saw a strong reduction in the amount of FLCN protein in the lungs of mice exposed to cigarette smoke for 6 months. They saw no difference in FLCN between the other two groups. This indicates that loss of FLCN protein is a consequence of long-term exposure to cigarette smoke.

The researchers also looked at the function of FLCN. They exposed cells grown in the lab to cigarette smoke and saw that there was more cell death compared to normal cells. They then changed these cells to either have more or less FLCN protein and repeated the experiment. The authors saw that there was more cell death in cells with less FLCN protein. The opposite effect was seen in cells with more FLCN protein. There was less cell death in these cells and so the authors suggested FLCN was able to protect against cell death caused by cigarette smoke.

The last part of the study was investigating how cigarette smoke exposure caused loss of FLCN protein. This could be due to there being a change in the amount of FLCN protein being made or something that causes the destruction of the existing FLCN protein. The authors checked the amount of FLCN mRNA (the precursor to protein) in the lung samples from people with and without COPD. They saw no difference in the amount of FLCN mRNA between the samples, indicating that the same amount of FLCN protein was being made. This led the researchers to hypothesise that FLCN protein was being specifically destroyed because of cigarette smoke exposure. Indeed, they identified a specific change to the FLCN protein that allowed degradation of the FLCN protein in response to cigarette smoke. They could stop the destruction of FLCN protein by either blocking the change or using a drug to inhibit the degradation pathway.

To find out more, we spoke to lead author of the paper Dr Toru Nyunoya:

“Our research results show that cigarette smoking depletes folliculin protein in lung cells.  So, we show that folliculin loss occurs in the presence of smoking habits, even in the absence of a hereditary cause.

According to the previous studies, people with BHD have pretty normal lung function.  However, I am not aware of any long-term studies to investigate the interaction between genetics (FLCN loss) and the environment (smoking). So, I still highly recommend for people with BHD to stop smoking.”

In summary, this study showed that cigarette smoking leads to a loss of FLCN protein. However, it did not explore whether loss of FLCN can cause COPD. Further work will need to be done to understand if and how loss of FLCN is linked to development of COPD. The studies that exist following people with BHD over time have not shown an increase in the rates of COPD. However, given the known risks associated with smoking, it would be advisable for BHD patients to avoid smoking.