Autophagy and its implication in human oral diseases

Abstract

Macroautophagy/autophagy is a conserved lysosomal degradation process essential for cell physiology and human health. By regulating apoptosis, inflammation, pathogen clearance, immune response and other cellular processes, autophagy acts as a modulator of pathogenesis and is a potential therapeutic target in diverse diseases. With regard to oral disease, autophagy can be problematic either when it is activated or impaired, because this process is involved in diverse functions, depending on the specific disease and its level of progression. In particular, activated autophagy functions as a cytoprotective mechanism under environmental stress conditions, which regulates tumor growth and mediates resistance to anticancer treatment in established tumors. During infections and inflammation, activated autophagy selectively delivers microbial antigens to the immune systems, and is therefore connected to the elimination of intracellular pathogens. Impaired autophagy contributes to oxidative stress, genomic instability, chronic tissue damage, inflammation and tumorigenesis, and is involved in aberrant bacterial clearance and immune priming. Hence, substantial progress in the study of autophagy provides new insights into the pathogenesis of oral diseases. This review outlines the mechanisms of autophagy, and highlights the emerging roles of this process in oral cancer, periapical lesions, periodontal diseases, and oral candidiasis.

Keywords: autophagy; oral cancer; oral candidiasis; periapical lesions; periodontal diseases.

Figure 1.

The mechanisms of autophagy. There are 3 primary forms of autophagy, including macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA), which mainly differ in their patterns of delivery and physiological functions. Macroautophagy (referred to hereafter as autophagy) involves the formation of multiple membrane structures ranging from the phagophore to autophagosome and autolysosome. The ULK complex is activated in response to signals such as starvation, and then binds to the PtdIns3K complex following MTOR suppression or AMPK activation. Upon induction, the orchestrated action of the ULK complex, the PtdIns3K complex and the ATG9 complex initiates the formation of the phagophore at the phagophore assembly site (PAS) in yeast or equivalent sites in more complex eukaryotes. The LC3 and ATG12 conjugation systems are key regulators in mediating the elongation of the phagophore into an autophagosome. Conversely, the major inhibitory factor MTOR suppresses autophagy under abundant nutrients conditions, which is regulated by class I PI3K and AKT signaling. The antiapoptotic proteins BCL2 and BCL2L1/BCL-xL negatively regulate autophagy by binding to BECN1. Moreover, DAPK promotes autophagy initiation through the phosphorylation of BECN1. In addition, autophagy can be pharmacologically induced or inhibited.

Figure 2.

Autophagy in human oral diseases. With regard to oral disease, inappropriate autophagy can consist of either activated autophagy or impaired autophagy, because this process has dual roles in various human oral diseases. Activated autophagy may play pathogenic roles through the regulation of cell death, or prevents the development of diseases in some conditions. Impaired autophagy can exacerbate disease at different stages, or serve as a potential therapeutic target. In oral cancer, activated autophagy acts as a cytoprotective mechanism, but can enhance radiosensitivity, whereas impaired autophagy augments chemotherapy. Autophagy may dampen periodontal inflammation and promote cell vitality in periapical lesions, or exacerbate periapical lesions and periodontal diseases through the interactions with apoptosis and the immune response. Meanwhile, the periodontopathic pathogen Porphyromonas gingivalis can exploit host cell autophagy for its own survival and replication. In addition, activated autophagy may promote long-term survival and invasive virulence of Candida albicans within the host. Pro: beneficial effects; Con: detrimental effects.