Lung health and disease

    van 't Wout E.F.A. | Leids Universitair Medisch Centrum | 5 november 2012 |

Lung Health and disease: endoplasmic reticulum (ER) stress, autophagy and apoptosis

Adapted with permission from 5.


Instead of providing a full overview of the whole meeting, this is a summary of two symposia that is most close to the topic of my own research: ER stress, autophagy, apoptosis and alpha1-antitrypsin deficiency. Many signaling pathways are involved to keep our lungs healthy. Over the past five years, some of these signaling pathways, namely ER stress, autophagy and apoptosis, attracted more and more attention, because these physiological responses might also eventually result in disease. To date, a broad range of various lung diseases are linked with ER stress, autophagy and apoptosis: lung fibrosis1, alpha-1-antitrpysin deficiency (AATD)2 and smoking related diseases as chronic obstructive pulmonary disease (COPD)3,4.

ER stress

The endoplasmic reticulum (ER) is the site of secretory and membrane protein folding and its quality control systems ensure that only properly folded proteins exit the organelle for secretion or integration into the cell membrane. Accumulation of unfolded or misfolded proteins in the ER induces “ER stress”, thereby activating intracellular signal transduction pathways collectively called the unfolded protein response (UPR). The aim of this complex cellular response is to maintain ER homeostasis initially by reducing the influx of newly synthesized proteins into the ER lumen and subsequently by enhancing the protein-folding capacity of the ER. In addition, cells remove terminally misfolded proteins by ER association degradation (ERAD) and/or autophagy5.
ERAD acts by the ubiquitin pathway and subsequently the proteasomal degradation by the proteasome. Sznajer4 explained that daily 5% of the proteins are degraded; therefore after roughly 20 days all proteins inside a cell are renewed (note: half-life of individual proteins may differ). He stated that aberrant protein degradation leads to disease: decreased degradation of for instance an oncogenic protein leads to cancer, however increased degradation of p53, a tumor suppressor gene, also leads to cancer. Furthermore, he showed the complexicity of the proteostasis network, that includes ERAD/proteasomal degradation and autophagy. He clarified that smoking misfolds and/or interferes with the function of proteins. As a result, both the ubiquitin proteasomal and autophagy pathways are triggered and serve as an important defense mechanism to keep the lung healthy.


A clear introduction in autophagy, or literally ‘self-eating’, was given by Dr. Choi6. He stated that autophagy is seen as a pro-survival function of a cell, especially during starvation. It is a highly conserved pathway and a critical adaptive response to cellular stress. A double-membrane structure engulfs damaged protein aggregates, which are too large for proteasomal degradation, to form an autophagosome which fuses with a lysosome. Inside this autophagolysosome, the damaged proteins are degraded and the important nutrients are kept for recycling.
Monick7 showed that cigarette smoke (CS) induces ubiquitination of proteins in lung epithelial cells, which is regulated by HDAC6. This conclusion was supported by studies of the same group on lung sections of COPD lungs which were loaded with autophagosomes and autophagolysosomes. Dr. Choi6 showed that LC3B deficient mice showed less autophagy and apoptosis after 6 months CS exposure. A physiological consequence is that these mice were more resistant to emphysema. Besides, CS leads to mitochondrial ROS production which may contribute to specific autophagy of mitochondria (mitophagy), which may in turn contribute to emphysema.

Alpha-1-antitrypsin deficiency: explaining the role of ER stress, autophagy and apoptosis in lung disease

Dr. Marciniak4 nicely showed that in AATD, polymers of the mutant Z-AAT within the ER of hepatocytes are cleared by ERAD and by autophagy (figure 1A and 1B). The misfolded Z-AAT does not activate the UPR, which might possibly be due to this efficient clearing. Interestingly, these polymers do activate NFB signalling via the poorly understood “ER overload response” (EOR), also known as the “ordered protein response” (OPR; figure 1B). Even more striking is the fact that Z-AAT polymers increase the cell’s sensitivity to ER stress upon a ‘second hit’, such as glucose starvation.
Dr. Sifers8 summarized the different treatment options for AATD: gene replacement therapy mostly done by adding the correct gene, enhancing degradation of misfolded Z-AAT or promoting conformational maturation. The disadvantages of the first one are the difficulty associated with trying to change a humane genome and, as proven, the ineffectiveness since the defect is still there as well. The latter two are novel strategies: in case of a loss of function, as in AATD, one has to enhance the deployment of active protein, by helping to fold the protein more efficiently, and thereby diminishing the degradation. In case of a gain of function, the Z-AAT protein needs to be efficiently degraded. Unfortunately, as one can imagine, the complexicity of the kinetics of these two Z-AAT forms delay the invention of effective therapies


figure 1. Adapted with permission from 5.
(A) The unfolded protein response (UPR)
with the ER associated degradation (ERAD)
(B) ER overload response (EOR) provoked
by polymers and the clearance of small and
bigger aggregates of Z-AAT by ERAD and
autophagy, respectively.


The described processes play an important role in lung health and disease. Unravelling the common pathways in different diseases and combining the knowledge about these processes could possibly give rise to new interventions.


1. Dr. W. Lawson, ATS 2012

2. Dr. S.J. Marciniak/Dr. R.N. Sifers, ATS 2012

3. Dr. I. Petrache, ATS 2012

4. Dr. J.I. Sznajer, ATS 2012

5. Dr. S.J. Marciniak, ATS 2012

6. Dr. A.M. Choi, ATS 2012

7. Dr. M.M. Monick, ATS 2012


Keyword: endoplasmic reticulum stress alpha-1

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