Malfolded protein structure and proteostasis in lung diseases

Abstract

Recent discoveries indicate that disorders of protein folding and degradation play a particularly important role in the development of lung diseases and their associated complications. The overarching purpose of the National Heart, Lung, and Blood Institute workshop on "Malformed Protein Structure and Proteostasis in Lung Diseases" was to identify mechanistic and clinical research opportunities indicated by these recent discoveries in proteostasis science that will advance our molecular understanding of lung pathobiology and facilitate the development of new diagnostic and therapeutic strategies for the prevention and treatment of lung disease. The workshop's discussion focused on identifying gaps in scientific knowledge with respect to proteostasis and lung disease, discussing new research advances and opportunities in protein folding science, and highlighting novel technologies with potential therapeutic applications for diagnosis and treatment.

Figure 1.

Key processes in the second half of the protein life cycle. (1) About 70% of newly synthesized proteins fold into functional proteins (assisted by chaperones); (2) a major knowledge gap exists about the role of misfolded or unfolded proteins in lung diseases; (3) genetic mutations or environmental risk factors can cause protein misfolding or unfolding; (4) the unfolded protein response refolds unfolded proteins using chaperones; (5) proteins that fail to refold are degraded by the ubiquitin proteasome system and autophagy–lysosome pathways.

Figure 2.

Proteostasis management of pulmonary health at a glance. Pulmonary health (inner circle) requires that constant pulmonary stresses (listed in the second layer) are accurately handled by proteostasis management pathways (listed in the third layer). The workshop identified knowledge gaps, timely scientific questions, and research tool needs to catalyze the application of proteostasis science to improve our understanding of lung disease pathophysiology and new approaches for treatment/management (outer layer and left panel).