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    • Autophagy is finalized through the

    2023-12-22

    Autophagy is finalized through the coordinated positioning and fusion of autophagosomes with lysosomes, during which an array of common and specific membrane traffic-associated proteins is mobilized. Among these proteins, small GTPases, like Rab7, Rab34, or Arl8, and their sesamin proteins, regulate fusion with lysosomes (Marwaha et al., 2017; McEwan et al., 2015). The Rab7 effector PLEKHM1 links LC3 on autophagosomes and the membrane tethering complex HOPS, which clusters autophagosomes and lysosomes (McEwan et al., 2015). HOPS then enables fusion of these vesicles by its interaction with the SNARE protein syntaxin 17 (Stx17) (Jia et al., 2017). Coordinated autophagosome and lysosome transport is therefore key for efficient fusion and autophagy-dependent antigen presentation (McEwan et al., 2015). Autophagosomes are precisely positioned using the microtubule network by molecules such as FYCO1, which binds plus-end-directed kinesins and is recruited to LC3 or PI3P enriched-membrane domains (Pankiv et al., 2010). Conversely, transport to the perinuclear area is mediated by the Rab7 effectors RILP and ORP1L, which recruit the minus-end-directed dynactin-dynein1 complex (Johansson et al., 2007) and ensure that autophagosomes cluster with lysosomes during starvation (Korolchuk et al., 2011). Interestingly, Rab34-dependent perinuclear clustering of lysosomes delays degradation of phagosomal cargo, thus enhancing CP1 in activated DCs, presumably by delaying complete antigen degradation (Alloatti et al., 2015). Conversely, Arl8 and BLOC-1 related complex (BORC) regulate lysosome peripheral positioning by promoting binding to kinesins (Jia et al., 2017). BORC depletion causes lysosome clustering, but also alters autophagy. This suggests that in APCs, CP1 and CP2 requirements might be mutually exclusive and that coordinated positioning of autophagosomes and lysosomes in response to extracellular cues is an essential part of the regulatory processes ensuring efficient and coordinated endogenous antigen presentation by APCs. Another example of the importance of autophagosome and lysosome positioning is their peripheral clustering in response to TLR triggering by microbe stimuli or DC long-term exposure to IL4 (Pierre et al., 1997; Terawaki et al., 2015). This implies that a strong coordination between immune activation and the positioning of endocytic organelles is required to achieve efficient antigen processing and presentation. Independently of rewiring mTORC1 signalling (Terawaki et al., 2015), a combination of GM-CSF and IL4 drives expression of RUN and FYVE domain-containing protein 4 (RUFY4) in DCs and alveolar macrophages. Its two globular domain are capable of binding small GTPases of the Rab family (RUN domain) and PI3P-containing membranes (FYVE domain). RUFY4 is the closest paralog of FYCO1, and interacts both with Rab7 and PI3P, pointing towards a function in autophagosome generation and/or fusion with lysosomes (Terawaki et al., 2016). RUFY4 augments Stx17-positive autophagosome formation, as well as perinuclear clustering of lysosomes, thus promoting LC3/Atg8 degradation and augmenting autophagy flux and CP2, as well as degradation of bacteria like Brucella abortus (Terawaki et al., 2015) and Salmonella enterica (Lassen et al., 2016). Thus, in some subsets of DCs and macrophages, RUFY4 harnesses the classical autophagy machinery to facilitate autophagosome flux and promote endogenous antigen presentation to CD4+ T cells.
    Conclusion
    Acknowledgements
    Introduction Phytochemicals (phyton means “plant” in Greek) are naturally occurring plant-based compounds. They are mostly composed of non-nutrient chemicals that are found in grains, vegetables, and fruits [1,2]. While over ten thousand phytochemicals have been identified, many others remain unknown and need to be identified [[1], [2], [3]]. Important groups of phytochemicals include phenolic compounds, alkaloids, terpenes, organosulfides, and glucosinolates [1,4,5]. The health benefits of phytochemicals are mostly associated with reducing the risk of developing diverse human diseases [3,5,6]. Such plant-based compounds are easily accessible, often with less toxic effects than synthetic molecules, and possess a wide range of biological and pharmacological effects, including anti-microbial, anti-tumoral, anti-mutagenic, and anti-oxidant or pro-oxidant activities [1,3,[5], [6], [7], [8], [9]]. Positive outcomes in clinical trials have led to the introduction of several phytochemicals into clinical practice in recent decades [6,10]. Particularly in cancer and other chronic diseases that are associated with excessive production of reactive oxygen species (ROS), both the anti-oxidant and pro-oxidant properties of phytochemicals can be utilized to prevent or eradicate cancer, respectively [3,9,[11], [12], [13]]. For example, enriched flavonoids from vegetables and fruits show potent ROS modulating and anti-cancer effects, alone or in combination with standard chemotherapy [14]. Mechanistically, the anti-cancer effects of phytochemicals are mostly mediated through induction of cell-cycle arrest or apoptotic cell death [[7], [8], [9],15]. In addition, recent studies have uncovered an important role for phytochemicals in governing the autophagy network [7,[15], [16], [17]]. In both normal and malignant cells, autophagy is induced by certain cellular stresses in order to preserve cell survival [18,19]. However, if the stress is not resolved, autophagy leads ultimately to programmed cell death [[18], [19], [20], [21], [22]]. In the context of cancer, autophagy acts as a tumor suppressor at early steps of tumorigenesis. Alternatively, autophagy can promote the growth and survival of established tumors during migration and epithelial-to-mesenchymal transition (EMT) as well as in response to chemotherapy [18,23,24]. In addition, autophagy is involved in cancer stem cell (CSC) survival, escape from immune surveillance and resistance to anoikis [25]. Therefore, autophagy with a double face role inhibits early stages of tumorigenesis while it becomes a driver of tumor invasion and metastasis at later stages [[26], [27], [28]]. Accordingly, manipulation of key factors in the autophagy pathway may be exploited as a novel therapeutic strategy for cancer therapies [20]. However, before proposing phytochemical as anti-cancer and autophagy-modulating agents, a better understanding of their complex mechanism of action needs to be addressed more deeply [5,16,17]. In this review, we represent common phytochemicals as a group of promising autophagy modulators and discuss their therapeutic importance in treating various cancers.