A Comprehensive Review of Autophagy and Its Various Roles in Infectious, Non-Infectious, and Lifestyle Diseases: Current Knowledge and Prospects for Disease Prevention, Novel Drug Design, and Therapy

Abstract

Autophagy (self-eating) is a conserved cellular degradation process that plays important roles in maintaining homeostasis and preventing nutritional, metabolic, and infection-mediated stresses. Autophagy dysfunction can have various pathological consequences, including tumor progression, pathogen hyper-virulence, and neurodegeneration. This review describes the mechanisms of autophagy and its associations with other cell death mechanisms, including apoptosis, necrosis, necroptosis, and autosis. Autophagy has both positive and negative roles in infection, cancer, neural development, metabolism, cardiovascular health, immunity, and iron homeostasis. Genetic defects in autophagy can have pathological consequences, such as static childhood encephalopathy with neurodegeneration in adulthood, Crohn's disease, hereditary spastic paraparesis, Danon disease, X-linked myopathy with excessive autophagy, and sporadic inclusion body myositis. Further studies on the process of autophagy in different microbial infections could help to design and develop novel therapeutic strategies against important pathogenic microbes. This review on the progress and prospects of autophagy research describes various activators and suppressors, which could be used to design novel intervention strategies against numerous diseases and develop therapeutic drugs to protect human and animal health.

Keywords: AKT/mTOR signaling pathway; apoptosis; autophagy inhibition; autophagy mechanism; autophagy-associated diseases; autosis; chaperone-mediated autophagy; iron homeostasis; macroautophagy; necroptosis; necrosis.

Figure 1

Different types of autophagy. Macroautophagy, microautophagy, and chaperone-mediated autophagy.

Figure 2

In chaperone-mediated autophagy (CMA), (1) KFERQ motif that is present in 30% of soluble cytosolic proteins (2) is recognized by cytosolic chaperone protein HSPA8/HSC70, which is present in a complex with other chaperone proteins. (3) Such recognized proteins bound to lysosomal receptor protein LAMP-2A. (4) Binding of the substrate with the LAMP-2A leads to oligomerization of receptors. (5) With the help of HSP90, the substrate is then unfolded and translocated through LAMP-2A-enriched translocation complex. (6) After reaching inside the lysosomes, the proteins are degraded (7), and the LAMP-2A receptors are disassembled.

Figure 3

Process of autophagosome formation. (1) Autophagy is inhibited by mTOR. (2) Various kinds of stress (hypoxia, oxidative stress, pathogen infection, endoplasmic reticulum stress or nutrient starvation conditions) inhibit mTOR, and the process of autophagy is initiated. (3) Assembly of ULK complex occurs, and the complex includes ULK-1, autophagy-related protein 13 (Atg13), Atg101 and FAK-Family Interacting Protein (FIP200). (4) The complex phosphorylates AMBRA1. (5) AMBRA1 activates PI3K complex encompassing Atg15, vacuolar protein sorting 15 (VPS15), VPS34, Beclin-1 and AMBRA1 which helps in nucleation. (6) Atg5-Atg12-Atg16 complex is recruited to phagophore and prevent premature fusion of vesicle to the lysosome. (7) LC3 is conjugated with PE by the ubiquitin-like system and (8) transformed into LC3-II with the help of Atg4, Atg7, and Atg3. (9) LC3-II is present on both the inner and outer surfaces of the autophagosome. (10) Atg 9 further elongates the membrane and forms intraluminal vesicles; also required for local acidification. (11) Atg5-Atg12-Atg16 complex is dissociated from the complete autophagosome (12).

Figure 4

Anti-bacterial role of autophagy. (1) Bcl-xL regulates the autophagy, and in Bcl-xL knockout cells, Streptococcus pyogenes infection is promoted. (2) Shigella flexneri invasion in non-phagocytic cells is dependent upon the type-III secretion system (T3SS) effector proteins. Following internalization nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) detect bacterial peptidoglycans and trigger pro-inflammatory immune response. Bacterial sensing inside the cell either by NLRs or sequestosome-1-like receptors (SLRs) recruits autophagy proteins including unc-51-like kinase (ULK) 1/2 with lipid kinase complexed with Beclin 1 and Atg16L1 to initiate membrane nucleation of the phagophore to engulf invading bacteria. (3) Group A Streptococcus species inhibits autophagy directly by suppressing the fusion of autophagosomes. (4) Bacillus amyloliquefaciens was found to stimulate autophagy by elevating the expression of Beclin 1 and Atg5-Atg12-Atg16 complex.

Figure 5

Proviral and anti-viral actions of autophagy.

Figure 6

Autophagy in tumor suppression. (1) The Atg5- or Atg7-deficient mice showed liver tumors, indicating that defective autophagy can affect the suppression of tumorigenesis. (2) Beclin 1 inhibits the growth of tumor in cell lines such as the breast cancer cell line, MCF-7, in which the expression of Beclin 1 was lower than in normal epithelial breast cells. (3) UVRAG protein could suppress tumorigenicity and proliferation of colon cancer cells in humans. (4) mTOR is implicated in cancer and its substrates include the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs) and the ribosomal S6 kinases (S6Ks) 1 and 2, which promote cell cycle progression. The mTOR, which is inhibited by rapamycin, induces autophagy. (5) A novel anti-cancer molecule, HA15, which targets HSPA5/BIP was shown to induce endoplasmic reticulum stress and increase the unfolded protein response, resulting in cancer cell death through autophagy and apoptosis.

Figure 7

Compounds that inhibit and activate autophagy. Autophagy inhibitors: 3-methyladenine inhibits PI3K. Bafilomycin A1 causes dissociation of the Beclin 1-Vps34 complex and prevents the formation of autolysosome. Chloroquine/hydroxychloroquine, NH₄Cl, and leupeptin rapidly neutralizing the acidic environment of the lysosome and are used to block lysosomal degradation of substrates. Leupeptin inhibits cysteine, serine and threonine peptidases, and hence blocking protein degradation at the last step of autophagy. Autophagy activators: rapamycin inhibits the mTOR. RAD001 and AP23573 are rapamycin derivatives having comparatively higher safely with minimum dose toxicities. Trehalose causes LC3-I to LC3-II conversion in an mTOR-independent pathway. Valproic acid increases LC3-II and Beclin 1 concentrations.