Autophagy in lung disease pathogenesis and therapeutics

Abstract

Autophagy, a cellular pathway for the degradation of damaged organelles and proteins, has gained increasing importance in human pulmonary diseases, both as a modulator of pathogenesis and as a potential therapeutic target. In this pathway, cytosolic cargos are sequestered into autophagosomes, which are delivered to the lysosomes where they are enzymatically degraded and then recycled as metabolic precursors. Autophagy exerts an important effector function in the regulation of inflammation, and immune system functions. Selective pathways for autophagic degradation of cargoes may have variable significance in disease pathogenesis. Among these, the autophagic clearance of bacteria (xenophagy) may represent a crucial host defense mechanism in the pathogenesis of sepsis and inflammatory diseases. Our recent studies indicate that the autophagic clearance of mitochondria, a potentially protective program, may aggravate the pathogenesis of chronic obstructive pulmonary disease by activating cell death programs. We report similar findings with respect to the autophagic clearance of cilia components, which can contribute to airways dysfunction in chronic lung disease. In certain diseases such as pulmonary hypertension, autophagy may confer protection by modulating proliferation and cell death. In other disorders, such as idiopathic pulmonary fibrosis and cystic fibrosis, impaired autophagy may contribute to pathogenesis. In lung cancer, autophagy has multiple consequences by limiting carcinogenesis, modulating therapeutic effectiveness, and promoting tumor cell survival. In this review we highlight the multiple functions of autophagy and its selective autophagy subtypes that may be of significance to the pathogenesis of human disease, with an emphasis on lung disease and therapeutics.

Keywords: Autophagy; Cigarette smoke; Lung disease; Mitophagy; Reactive oxygen species.

Graphical abstract

Fig. 1

Sequence of the (Macro)-autophagy pathway. Autophagy proceeds through a series of steps that begin with the formation of the isolation membrane at a pre-autophagosomal site. The nascent autophagic membrane elongates to form a double-membrane autophagosome which encompasses a region of cytoplasm, which may include a specific cellular substrate (e.g., damaged mitochondria or aggregated protein). Upon maturation, the autophagosome containing the isolated cargo fuses with the lysosome to form a single-membraned autolysosome. The autophagosomal cargo is then enzymatically degraded in this compartment. The degradation products which may include free amino acids, fatty acids, and nucleotides, are released to the cytoplasm by the action of lysosomal permeases, where they may be reutilized for anabolic pathways.

Fig. 2

Molecular regulation of autophagy. Autophagy responds to negative regulation by growth factor stimuli that regulate the Class I phosphatidylinositol-3-kinase (PI3K/AKT) pathway, which upregulates the mTOR pathway. mTOR resides in a macromolecular complex (mTORC1): this multi-protein complex is activated by nutrient associated signals including amino acids and growth factors, and negatively regulates autophagy by interacting with the ULK1 complex. Autophagy also responds to regulation by depletion of cellular energy charge through the increased activity of the 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK). In response to elevated AMP levels, AMPK inactivates mTORC1 and activates ULK1, which can activate Beclin1 and promote the trafficking of mATG9. The initiation of autophagosome formation is also regulated by the autophagy protein Beclin 1 (Atg6). Beclin 1 associates with a macromolecular complex that includes hVps34, a class III phosphatidylinositol-3 kinase (PI3KC3), p150, and ATG14L. The Beclin1 complex produces PI3P which recruits assessory factors in autophagosome formation, including WIPI2. Autophagosome elongation requires two ubiquitin-like conjugation systems, the ATG5-12 conjugation system, and the ATG8 (LC3) conjugation system. Autophagy protein LC3-II remains associated with the maturing autophagosome.

Fig. 3

Significance of autophagy in pulmonary disease. Autophagy may exert multiple functions that may be relevant to the pathogenesis of lung disease. These include the general protective effects of autophagy in metabolic recycling, the regulation of inflammation, and the regulation of cell death pathways. The protective aspects of autophagy against carcinogenesis in primary cells, may also provide a paradoxical survival advantage to growing tumors. In certain diseases such as fibrotic lung diseases, impaired autophagy may influence the pathogenesis. Specialized subtypes of selective autophagy may gain importance in select pulmonary disorders. The xenophagy function of autophagy may be important in infectious diseases and sepsis. The mitophagy and ciliaphagy programs have recently been implicated in the pathogenesis of chronic lung disease.