# Cellular Self-Digestion and Persistence in Bacteria
## 6 Importance of Autophagy in Drug Tolerance  
Given the similarities between prokaryotic and eukaryotic persisters [259], it is appealing to draw parallels between bacterial and mammalian persister cells and to expect that knowledge gained from one will enrich our understanding of the other [55]. Although the \"persister\" term has recently been used in cancer research [28; 29; 30], drug tolerance mechanisms in tumor cells that are not mediated by heritable mutations have long been known in the field. Indeed, a lot of mechanisms associated with bacterial persisters have been already identified in drug-tolerant cancer cells, such as enhanced efflux activities (e.g., higher rate of drug export from the cell), enhanced repair activities (e.g., efficient repair of drug-induced cell damage), active bypass pathways (e.g., alternative pathways to avoid the drug target), or altered cell metabolism (e.g., a distinct set of active metabolic reactions) [260; 261; 262]. There are also similarities between cellular self-digestion and autophagy. However, due to the lack of organelles and complex structures in bacteria, a compartmentalized autophagy is not observed in these cells. Autophagy in eukaryotes promotes cell survival and generates energy and intermediate molecules for vital anabolic processes by degrading cellular components in lysosomes [263]. Within these lysosomes, proteins, DNAs, RNAs, polysaccharides, and lipids are hydrolyzed by a diverse range of degradative enzymes [264]. Lysoszymes contain approximately 50 different hydrolytic enzymes [265], including the Lon protease [266], which was first identified in bacteria and is known to be a crucial persistence molecule, as discussed above. Depending on the mechanism that mediates transport of cytosolic cargo to lysosomes, eukaryotic autophagy can be categorized into three major types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) [267]. Although, macroautophagy and microautophagy are similar in terms of initiation, termination, and capacity for the sequestration of large structures, they are distinct pathways [268]. The formation of autophagosomes is a hallmark of macroautophagy and consists of several distinct steps (i.e., nucleation, elongation, and closure of the double-membared vesicle) [269]; these are mediated by a cluster of proteins known as autophagy-related proteins (ATGs). Once the autophagosome is formed, it fuses with a lysosome, and a single-membrane vesicle (i.e., the autophagic or Cvt body) is released into the lumen. In contrast, during microautophagy, cargos are directly engulfed and taken up by the lysosomal membrane as result of local deformation and rearrangement of the membrane, allowing the cytosolic cargos to be degraded by vacuolar hydrolases and enzymes within the lysosome [264]. The resulting macromolecules such as amino acids or fatty acids from the lysosomal degradation are recycled back into the cytosol via membrane permeases to be used in anabolic processes. In CMA, the degradation of soluble cytosolic proteins in lysosomes is highly selective. Substrate selection in CMA is regulated by cytosolic chaperones that recognize pentapeptidemotifs in the amino acid sequence of the substrate proteins [270]. In this type of autophagic process, substrates are not engulfed, but, instead, are translocated across the lysosomal membrane in a receptor-mediated manner [271]. In eukaryotes, the autophagy regulatory network is highly complex and tightly connected to redundant signaling pathways, some of which are related to the cell cycle and proliferation, including the mammalian target of rapamycin kinase (TOR), nuclear factor of kappa light polypeptide gene enhancer (NFKB/NF-kB), mitogen-activated protein kinase (MAPK), and tumor protein p53 (TP53) cascades [272]. Notably, autophagy may play a critical role in cancer persistence, as there is evidence for reciprocal interactions between autophagy and cell cycle arrest, the hallmark of cancer persistence [273].