Understanding the molecular regulatory mechanisms of autophagy in lung disease pathogenesis

Abstract

Lung disease development involves multiple cellular processes, including inflammation, cell death, and proliferation. Research increasingly indicates that autophagy and its regulatory proteins can influence inflammation, programmed cell death, cell proliferation, and innate immune responses. Autophagy plays a vital role in the maintenance of homeostasis and the adaptation of eukaryotic cells to stress by enabling the chelation, transport, and degradation of subcellular components, including proteins and organelles. This process is essential for sustaining cellular balance and ensuring the health of the mitochondrial population. Recent studies have begun to explore the connection between autophagy and the development of different lung diseases. This article reviews the latest findings on the molecular regulatory mechanisms of autophagy in lung diseases, with an emphasis on potential targeted therapies for autophagy.

Keywords: COPD; apoptosis; autophagosome; autophagy; pulmonary diseases.

Figure 1

Autophagy is involved in the development and progression of multiple diseases.

Figure 2

Phases and Classification of Autophagy. According to the different ways of transporting substrates to lysosomes, autophagy can be divided into three main ways: macroautophagy, microautophagy and CMA. Macroautophagy: It starts as autophagy-related substances accumulate around misfolded and aggregated proteins, pathogens, non-essential amino acids, etc. to form a barrier membrane. Dysfunctional organelles as well as proteins are surrounded by an isolation membrane and gradually form a bilayer membrane structure, called autophagosomes. The outer membrane of autophagosomes then fuses with lysosomes, and internal material is degraded in autolysosomes. Microautophagy: The process by which membranes of lysosomes encapsulate cargo by direct protrusion or invagination and are degraded in lysosomes. CMA: Substrate proteins containing the KFERQ-like pentapeptide sequence are first recognized by HSC70, then bind to LAMP-2A on the lysosomal membrane and enter the lysosome and eventually are degraded. CMA, Chaperone-mediated autophagy; HSC70, Heat shock cognate protein 70; LAMP-2A, Lysosomal membrane-associated protein 2A.

Figure 3

Signaling pathways for autophagy. The process of autophagy is regulated by many signaling pathways (as shown), and there is also complex crosstalk between various pathways. Two ubiquitin-like conjugation systems involved in the formation of autophagosome: In the first system, the ubiquitin-like protein Atg12 is enzymatically coupled to Atg5 by Atg7 (E1 ubiquitin-activating enzyme-like) and Atg10 (E2 ubiquitin-conjugating enzyme-like) to produce the Atg5-Atg12 complex. The Atg5-Atg12 complex interacts with Atg16L1 to form a complex that plays a role in the formation of autophagic membranes. As part of the maturation process, these factors are separated from autophagosomes. The second coupling system requires the ubiquitin-like protein LC3. LC3 and its homologues, including the isozymes of LC3 and associated proteins (e.g., GABARAP), are modified by cellular lipid PE. An important regulatory step in the formation of autophagosomes is the transformation of LC3-I (free form) to LC3-II (PE conjugated form). The precursor form of LC3 is cleaved by the protease ATG4B to yield LC3- I (not shown). ATG7 and ATG3 participate in conjugating PE with LC3-I to LC3-II. LC3-II cytoplasmic redistribution, characterized by punctate LC3 staining, is indicative of autophagosome formation. GABARAP, (GABA type A receptor-associated protein); LC3, (Microtubule-associated protein 1 light chain 3; PE, (Phosphatidylethanolamine).

Figure 4

Autophagy and apoptosis. In endogenous apoptosis, the interaction of autophagic proteins with apoptotic proteins regulates this process. Bcl-2 family members, including Bcl-2 and Bcl-XL, can directly interact with Beclin 1 by binding to the BH3 domain. The JNK pathway promotes autophagy by preventing the association between Beclin 1 and Bcl-2 family proteins. AMPK also dissociates the Bcl-2-Beclin1 complex and promotes Beclin1-PI3K complex formation. Apoptosis signaling pathways may be affected by various autophagic proteins such as Atg5. Proteolytic fragments of Atg5 are able to promote apoptosis by inhibiting Bcl-XL. In extrinsic apoptosis, key components of DISC regulate autophagy during this process. Apoptosis and autophagy are affected by mutations in FADD, which create DD. The mutant (FADD-DD) was recruited to DISC in the absence of DED. By interacting with caspase 8 precursor and c-FLIP, this domain prevents the development of death receptor-induced apoptosis, while it can lead to excessive autophagy in epithelial cells and T cells. Atg5 can form a complex with FADD to affect the apoptosis process. AMPK, (Adenosine 5’-monophosphate-activated protein kinase); Bcl-2, (B-cell lymphoma-2); BH3, (Bcl-2 homolog3r); Caspase, (Cysteine protease); c-FLIP, (Cellular FADD-like IL-1β-converting enzyme-inhibitory protein); DD, (Death domain); DED, (Death effector domain); DISC, (Death-inducing signaling complex); JNK, (c-Jun-NH2-terminal kinase).

Figure 5

Autophagy in inflammation and immunity. Autophagy proteins play a role in inducing and suppressing immune and inflammatory responses, and immune and inflammatory signals play a role in inducing and inhibiting autophagy. Autophagic proteins play an important role in adaptive immunity, mainly including maintaining the normal number and function of immune-related cells such as B1a B cells, CD4⁺ T cells, and CD8⁺ T cells. Autophagy also plays a role in innate immunity when pathogens such as bacteria and viruses invade the human body. However, some pathogens are able to achieve their own survival by inhibiting, evading or even utilizing the autophagic process. Autophagy pathways and associated proteins also play crucial roles in regulating inflammatory responses. Increased transcription of pro-inflammatory cytokines and adipokines has been observed in mouse Paneth cells (Atg16L1HM), which contribute to the development of inflammation. Inflammasomes are important substances in the development of inflammation, and inflammasomes activated by various factors mediate the degradation and activation of caspase-1 and ultimately promote the synthesis and secretion of inflammatory factors (IL-1β and IL-18). Autophagy also removes cell debris generated by apoptosis, which in turn inhibits tissue inflammation.

Figure 6

Autophagy in lung diseases. In this figure, we summarize the pathogenesis related to the process of autophagy in six pulmonary diseases: COPD, CF, IPF, PTB, PH, and NSCLC. CF, (Cystic fibrosis); COPD, (Chronic obstructive pulmonary disease); IPF, (Idiopathic pulmonary fibrosis); NSCLC, (Non-small cell lung cancer); PH, (Pulmonary hypertension); PTB, (Pulmonary tuberculosis).