3. Mechanisms of Autophagy Dysfunction
Despite the importance of autophagy, there are many conditions where this process can become dysfunctional, leading to various pathological states. In the lungs, the major sources of autophagy dysfunction includes first- and second-hand cigarette smoke (CS) exposure and aging [35,62,93]. Studies have demonstrated that CS exposure can decrease the expression of transcription factor-EB (TFEB), a master autophagy regulator [34,35]. This occurs by the dysfunctional processing of TFEB in response to CS, causing the perinuclear localization of TFEB which prevents the activation of autophagy [62]. This CS-induced autophagy impairment of TFEB leads to impaired bacterial clearance [22,33,34,35]. Furthermore, there is evidence that CS exposure increases the accumulation of ubiquitinated proteins and p62 (a marker of autophagy impairment) in aggresome bodies, further impairing autophagy [22,34]. These deleterious effects of CS exposure on autophagy have also been demonstrated to be present in eCV exposure, which similarly impairs autophagy through the accumulation of aggresome bodies [39,94]. Furthermore, increasing the severity of pulmonary dysfunction and autophagy impairment has been observed to statistically correlate directly with increased levels of aggresome bodies [36], demonstrating its potential as a prognostic biomarker. Hence, CS exposure demonstrates a common, but preventable way autophagy can be impaired in individuals. Notably, CS exposure accelerates lung aging, known to be initiated by autophagy decline, which can exacerbate infections [33].
In addition to smoking, autophagy can be impaired by infectious agents. Due to the conserved nature of autophagy, many organisms have adapted and evolved mechanisms to impair autophagy in order to infect their host. For example, studies have demonstrated that the influenza virus promotes its own survival by preventing autophagolysosome formation; thus, leading to autophagy impairment via aggresome accumulation [41,85,95]. Influenza has also been found to prevent the autophagy-dependent presentation of viral antigens necessary to mount an immune response [10]. Similarly, investigations have found that severe acute respiratory syndrome coronavirus (SARS-CoV) can inhibit autophagolysosome formation with trans membrane papain-like protease 2 (PLP2-TM) to provoke phagolysosome accumulation causing autophagy impairment [96]. Additionally, the nonstructural protein 6 (NSP6) of coronaviruses has also been observed to restrict autophagosome development to prevent cells from inhibiting coronavirus replication [97].
However, autophagy inhibition by pathogens is not something that is unique to viruses. Legionella pneumophilia (L. pneumophilia) has been found to delay the progression of infected autophagosomes to lysosomes to allow the bacteria to develop an acid-tolerant state prior to autophagolysosome formation [98,99]. This delay allows L. pneumophilia to replicate in the acidic environment of the autophagolysosome [99] and cause infection within the host. This mechanism of autophagy impairment is not unique to L. pneumophilia and has been observed as a common mechanism of bacteria to promote their invasion and replication [7,100,101]. M. tuberculosis has also been observed to impair phagolysosome formation; meanwhile, other studies have further demonstrated that M. tuberculosis has the ability to activate cellular pathways that inhibit autophagy within macrophages to promote intracellular survival [61]. Hence, there are various organisms that can infect humans and cause autophagy dysfunction for their own survival.
The expression of CFTR has been shown to influence autophagy as discussed above. One mechanism of decreased CFTR expression is due to the genetic defects found in CF, where the most common mutation seen in these patients is ΔF508-CFTR [102,103,104]. Studies have demonstrated that ΔF508-CFTR causes protein misfolding that forms aggregates potentially impairing cellular proteostasis [20,42,53,61]. This dysfunction caused by ΔF508-CFTR includes autophagy dysfunction and decreases pathogen clearance in the airways of patients with CF [53]. Similar findings were observed in macrophages with dysfunctional CFTR [105,106].
Along with the genetic mechanism of CFTR dysfunction present in CF that can impair autophagy, CFTR function has been shown to be diminished by CS exposure [40,107,108,109], which is known as acquired CFTR dysfunction. One mechanism of CS-induced CFTR dysfunction leading to impaired autophagy is through increased ceramide accumulation as a result of altered sphingolipid homeostasis in COPD patients [22,93,110]. CS exposure can also increase ROS which causes CFTR to accumulate in aggresome bodies and impair autophagy [42,62]. Thus, both genetic mechanisms and CS exposure or environmental factors play a critical role in CFTR dysfunction and the resulting autophagy impairment (Figure 1).