Autophagy: a core cellular process with emerging links to pulmonary disease

Abstract

Autophagy is a highly conserved homeostatic pathway by which cells transport damaged proteins and organelles to lysosomes for degradation. Dysregulation of autophagy contributes to the pathogenesis of clinically important disorders in a variety of organ systems but, until recently, little was known about its relationship to diseases of the lung. However, there is now growing evidence at the basic research level that autophagy is linked to the pathogenesis of important pulmonary disorders such as chronic obstructive pulmonary disease, cystic fibrosis, and tuberculosis. In this review, we provide an introduction to the field of autophagy research geared to clinical and research pulmonologists. We focus on the best-studied autophagic mechanism, macroautophagy, and summarize studies that link the regulation of this pathway to pulmonary disease. Last, we offer our perspective on how a better understanding of macroautophagy might be used for designing novel therapies for pulmonary disorders.

Figure 1.

Schematic depiction of the three known autophagy pathways. (A) Chaperone mediated autophagy based on Dice (120). (B) Microautophagy based on Sahu and colleagues (20). (C) Macroautophagy based on Mizushima (121).

Figure 2.

Proposed molecular mechanism for autophagosome formation, based on Itakura and Mizushima (122), Hayashi-Nisino and colleagues (45, 46), and Weidberg and colleagues (52). AMPK = AMP-activated protein kinase; ATG = autophagy-related protein; AV = autophagic vacuole; DFCP1 = double FYVE-containing protein 1; ER = endoplasmic reticulum; FIP200 = FAK [focal adhesion kinase] family interacting protein of 200 kD; GABARAP = γ-aminobutyric acid type A receptor–associated protein; GATE16 = Golgi-associated ATPase enhancer of 16 kD; mTOR = mammalian target of rapamycin; PAS = phagophore assembly site; PI3 = 3-phosphatidylinositol; WIPI = WD repeat domain, phosphoinositide-interacting protein.

Figure 3.

Schematic of the macroautophagy pathway. Red circles depict LC3b; orange ovals depict mitochondria; yellow hexagons and black dots depict ribosomes and cytosolic proteins, respectively. A representative Western blot of LC3b-I and LC3b-II is displayed at lower left.