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Proteostasis in pediatric pulmonary pathology

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ABSTRACT

Protein homeostasis describes the tight supervision of protein synthesis, correct protein maturation and folding, as well as the timely disposal of unwanted and damaged proteins by the ubiquitin-proteasome pathway or the lysosome-autophagy route. The cellular processes involved in preservation of protein homeostasis are collectively called proteostasis. Dysregulation of proteostasis is an emerging common pathomechanism for chronic lung diseases in the adult and aged patient. There is also rising evidence that impairment of protein homeostasis contributes to early sporadic disease onset in pediatric lung diseases beyond the well-known hereditary proteostasis disorders such as cystic fibrosis and alpha-1 antitrypsin (AAT) deficiency. Identifying the pathways that contribute to impaired proteostasis will provide new avenues for therapeutic interference with the pathogenesis of chronic lung diseases in the young and adult. Here, we introduce the concept of proteostasis and summarize available evidence on dysregulation of proteostasis pathways in pediatric and adult chronic lung diseases.

No MeSH data available.


Life and death of proteins. Proteins are synthesized as a linear amino acid chain at the ribosomes and fold into their native structure with the assistance of chaperones. Misfolded proteins in the cytosol or in cellular compartments, such as ER and mitochondria, are recognized by chaperones which support their refolding into the native structure. If misfolded proteins cannot be properly refolded, they are targeted for degradation mainly by the ubiquitin-proteasome system. For proteasomal degradation, proteins are tagged with a polyubiquitin chain and subsequently degraded by the proteasome into small peptides. Misfolded proteins of the ER or at the mitochondria are retro-translocated into the cytosol and transported to the proteasome for degradation with the help of VCP/p97. Aggregated proteins are engulfed by the autophagosome and degraded after fusion of lysosomes with the autophagosome. Degradation products of the proteasome and the autophagy pathway are mainly recycled as amino acids for protein synthesis.
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Fig1: Life and death of proteins. Proteins are synthesized as a linear amino acid chain at the ribosomes and fold into their native structure with the assistance of chaperones. Misfolded proteins in the cytosol or in cellular compartments, such as ER and mitochondria, are recognized by chaperones which support their refolding into the native structure. If misfolded proteins cannot be properly refolded, they are targeted for degradation mainly by the ubiquitin-proteasome system. For proteasomal degradation, proteins are tagged with a polyubiquitin chain and subsequently degraded by the proteasome into small peptides. Misfolded proteins of the ER or at the mitochondria are retro-translocated into the cytosol and transported to the proteasome for degradation with the help of VCP/p97. Aggregated proteins are engulfed by the autophagosome and degraded after fusion of lysosomes with the autophagosome. Degradation products of the proteasome and the autophagy pathway are mainly recycled as amino acids for protein synthesis.

Mentions: Maintenance of a functional proteome and protein interaction network is essential for the survival of cells and organisms [1]. The cellular processes involved in preservation of this protein homeostasis are collectively called proteostasis. It covers all steps in the life of a protein, i.e., protein synthesis, correct protein maturation and folding, as well as the timely disposal of unwanted and damaged proteins by the ubiquitin-proteasome pathway or the lysosome-autophagy route (FigureĀ 1). Dysfunctional proteostasis is emerging as a key and common pathomechanism for chronic lung diseases [2]. The range of lung disorders in which aberrant protein homeostasis has been implicated covers both pediatric and adult lung diseases that occur due to genetic, environmental, or idiopathic causes. The list includes chronic obstructive pulmonary disease (COPD) due to cigarette smoking or alpha-1 antitrypsin (AAT) deficiency, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), and some allergic airways diseases. Identifying the pathways of impaired proteostasis is central to interfere with the pathogenesis of chronic lung diseases in the young and adult [3].Figure 1


Proteostasis in pediatric pulmonary pathology
Life and death of proteins. Proteins are synthesized as a linear amino acid chain at the ribosomes and fold into their native structure with the assistance of chaperones. Misfolded proteins in the cytosol or in cellular compartments, such as ER and mitochondria, are recognized by chaperones which support their refolding into the native structure. If misfolded proteins cannot be properly refolded, they are targeted for degradation mainly by the ubiquitin-proteasome system. For proteasomal degradation, proteins are tagged with a polyubiquitin chain and subsequently degraded by the proteasome into small peptides. Misfolded proteins of the ER or at the mitochondria are retro-translocated into the cytosol and transported to the proteasome for degradation with the help of VCP/p97. Aggregated proteins are engulfed by the autophagosome and degraded after fusion of lysosomes with the autophagosome. Degradation products of the proteasome and the autophagy pathway are mainly recycled as amino acids for protein synthesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4530569&req=5

Fig1: Life and death of proteins. Proteins are synthesized as a linear amino acid chain at the ribosomes and fold into their native structure with the assistance of chaperones. Misfolded proteins in the cytosol or in cellular compartments, such as ER and mitochondria, are recognized by chaperones which support their refolding into the native structure. If misfolded proteins cannot be properly refolded, they are targeted for degradation mainly by the ubiquitin-proteasome system. For proteasomal degradation, proteins are tagged with a polyubiquitin chain and subsequently degraded by the proteasome into small peptides. Misfolded proteins of the ER or at the mitochondria are retro-translocated into the cytosol and transported to the proteasome for degradation with the help of VCP/p97. Aggregated proteins are engulfed by the autophagosome and degraded after fusion of lysosomes with the autophagosome. Degradation products of the proteasome and the autophagy pathway are mainly recycled as amino acids for protein synthesis.
Mentions: Maintenance of a functional proteome and protein interaction network is essential for the survival of cells and organisms [1]. The cellular processes involved in preservation of this protein homeostasis are collectively called proteostasis. It covers all steps in the life of a protein, i.e., protein synthesis, correct protein maturation and folding, as well as the timely disposal of unwanted and damaged proteins by the ubiquitin-proteasome pathway or the lysosome-autophagy route (FigureĀ 1). Dysfunctional proteostasis is emerging as a key and common pathomechanism for chronic lung diseases [2]. The range of lung disorders in which aberrant protein homeostasis has been implicated covers both pediatric and adult lung diseases that occur due to genetic, environmental, or idiopathic causes. The list includes chronic obstructive pulmonary disease (COPD) due to cigarette smoking or alpha-1 antitrypsin (AAT) deficiency, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), and some allergic airways diseases. Identifying the pathways of impaired proteostasis is central to interfere with the pathogenesis of chronic lung diseases in the young and adult [3].Figure 1

View Article: PubMed Central

ABSTRACT

Protein homeostasis describes the tight supervision of protein synthesis, correct protein maturation and folding, as well as the timely disposal of unwanted and damaged proteins by the ubiquitin-proteasome pathway or the lysosome-autophagy route. The cellular processes involved in preservation of protein homeostasis are collectively called proteostasis. Dysregulation of proteostasis is an emerging common pathomechanism for chronic lung diseases in the adult and aged patient. There is also rising evidence that impairment of protein homeostasis contributes to early sporadic disease onset in pediatric lung diseases beyond the well-known hereditary proteostasis disorders such as cystic fibrosis and alpha-1 antitrypsin (AAT) deficiency. Identifying the pathways that contribute to impaired proteostasis will provide new avenues for therapeutic interference with the pathogenesis of chronic lung diseases in the young and adult. Here, we introduce the concept of proteostasis and summarize available evidence on dysregulation of proteostasis pathways in pediatric and adult chronic lung diseases.

No MeSH data available.