Chapter Four - The interplay between selective types of (macro)autophagy: Mitophagy and xenophagy

During evolution, cells have developed a plethora of mechanisms to adapt to endogenous deleterious stressors (i.e. DNA damage, proteotoxic stress) and changing environments (i.e. nutrients depletion or hypoxic conditions). Macroautophagy (thereafter referred to as autophagy) is a key adaptive mechanism to overcome these insults. A plethora of distinct autophagic procedures have been defined, including xenophagy and mitophagy, among others (Galluzzi et al., 2017). Here we report the most recent advances in the study of autophagy, with special focus in xenophagy and mitophagy and how their crosstalk regulates a wide range of cellular processes, including ageing, metabolism, and cancer. The review aims to offer a general overview of these topics, with special focus on (but not limited to) the literature from the last 5 years.

Autophagy is a physiological cellular process for the intracellular degradation of aberrant proteins, damaged organelles or intracellular pathogens. In addition to protein aggregates, injured organelles and infectious agents, autophagy can be activated by a plethora of stimuli, including nutrient starvation, growth factor deprivation, hypoxia, reactive oxygen species and DNA damage. Thus, autophagy entails an adaptive mechanism to alleviate cellular stresses, obtain energy, and, ultimately, promote cell survival. Canonical autophagy is mediated by double membrane vesicles called autophagosomes that sequester cellular components and deliver them to the lysosome for degradation. Autophagy plays a key role in many biological processes, ranging from development to tumorigenesis. Originally, autophagy was perceived as a bulk non-selective process, through which cytoplasmic material is indiscriminately recycled to provide energy and building blocks. Nevertheless, it is now appreciated that autophagy operates in a highly selective manner, and a variety of selective autophagy pathways have been defined. According to the cargo of selective autophagy, these include mitophagy, nucleophagy, pexophagy, reticulophagy/ER-phagy, lipophagy, aggrephagy, ferritinophagy and more. Apart from degrading endogenous material, autophagy (originating from the Greek words “auto” meaning “self” and “phagy” meaning eating) may also target exogenous material, including bacteria, viruses and fungi, in a process termed xenophagy (originating from “xeno” meaning “foreign”) (Deretic and Kroemer, 2022; Gatica et al., 2018; Yu et al., 2018).

Mitophagy is a type of selective autophagy that clears dysfunctional, old or excessive mitochondria by targeting them for degradation in autophagosomes. Hence, mitophagy promotes cellular homeostasis by maintaining the integrity of the mitochondrial pool and/or adapting the mitochondrial content to certain stresses, similar to those triggering autophagy (Markaki and Tavernarakis, 2020). As expected, mitophagy molecular cascades overlap with those involved in other types of selective autophagy, as well as in bulk autophagy. Autophagy and mitophagy initiation seem to be triggered, at least partially, by the same molecular components (reviewed in (Zachari and Ktistakis, 2020)). In autophagy, the mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) transmit signals of stress via its downstream effector the unc-51 like autophagy activating kinase 1 (ULK1) complex. Thus, upon certain stresses, ULK1 complex promotes autophagy initiation. Similarly, the ULK1 complex has been described to coordinately colocalize with autophagy-related protein 9 (ATG9) vesicles along the endoplasmic reticulum (ER). ATG9 vesicles are another source of lipid membrane that is included in new autophagosomes and mitophagosome (i.e. autophagosomes engulfing mitochondria) initiation (Lou et al., 2020). Therefore, both ULK1 complex and ATG9 vesicles are key inducers for mitophagosome initiation (Yamano et al., 2018). The associated ATG machinery also overlaps with that used in autophagy and, in a similarly way to autophagy, once the machinery is properly localized, the phagophore engulfing the mitochondria elongates and matures via the addition of lipids until it is ready to be closed by the endosomal sorting complex (reviewed in Killackey et al., 2020). Mitophagy is promoted via ubiquitination of outer mitochondrial membrane proteins or through the function of selective mitophagy receptors, such as BCL2 and adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) and Nip3-like protein X (NIX)/BNIP3-like protein (BNIP3L), as recently reviewed elsewhere (Onishi et al., 2021).

Xenophagy is a type of selective autophagy targeting invading pathogens, acting via ubiquitin-dependent and independent pathways. During host cell invasion, bacteria are initially encapsulated into single membrane vacuolar compartments. However, invading pathogens may breach the vacuole and gain access to the nutrient rich cytosol. As a result, pathogens themselves, as well as the internal components of the vacuolar membrane, get exposed to the cytosol, where they are recognized as intruders by diverse host systems and initiate multiple host defense pathways (Reggio et al., 2020). Glycans are key constituents of the vacuolar membrane that are recognized by galectins, which are host proteins that act as bacterial sensors. Several galectins, including galectin 3, galectin 8 and galectin 9 are involved in xenophagic responses in multiple ways, for instance by recruiting autophagy receptors, such as nuclear dot protein 52 (NDP52)/calcium binding and coiled-coil domain 2 (CALCOCO2) and tripartite motif-containing (TRIM) proteins (Chauhan et al., 2016; Johannes et al., 2018; Thurston et al., 2012). These receptors directly bind to members of the microtubule associated protein 1 light chain 3 (MAP1LC3) and GABA type A receptor-associated protein (GABARAP) families and deliver the cargo to autophagosomes. Furthermore, additional components of the vacuolar compartment can recruit core autophagy proteins to induce xenophagy. For example, the V-ATPase of the vacuolar membrane physically interacts with autophagy related 16 like 1 (ATG16L1) through its WD40 domain, to promote bacterial autophagy during Salmonella infection (Xu et al., 2019).

Recent evidence supports that multiple autophagy receptors may be recruited in a sequential fashion on bacteria-containing vacuoles or intracellular pathogens. Toll interacting protein (TOLLIP), an autophagy receptor previously shown to be involved in the clearance of protein aggregates, was recently identified as a critical regulator of bacterial autophagy during group A Streptococcus (GAS) infection. Specifically, TOLLIP accumulates on to GAS-containing vacuoles prior to their rupture, where it promotes the recruitment of additional autophagy receptors, such as neighbor of BRCA1 gene 1 (NBR1), tax1 binding protein 1 (TAX1BP1) and  NDP52, as well as several galectins, to promote xenophagy (Lin et al., 2020).

Apart from delivering the cargo into autophagosomes, novel studies have established unexpected roles for cargo receptors in xenophagy. For instance, during Salmonella infection the autophagy receptor NDP52 orchestrates the de novo biogenesis of phagophores in the bacterial vicinity and juxtapositions phagophores and cargos. Mechanistically, NDP52 forms a tripartite complex with 200 kDa FAK family kinase-interacting protein (FIP200) and similar to NAP1 TBK1 adaptor (SINTBAD) – NAK associated protein 1 (NAP1) via its N-terminal SKIP carboxyl homology (SKICH) domain, independently of its LC3-interacting region (LIR). These in turn recruit ULK1 and tank-binding kinase 1 (TBK1) respectively to initiate bacterial autophagy (Ravenhill et al., 2019).

留言 (0)

沒有登入
gif