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    • In a recent study Tomkins et al analyzed

    2020-08-10

    In a recent study, Tomkins et al. [7] analyzed the protein-protein interaction network of ROCO proteins. Based on a database analysis, and only taking into account interactions reported in at least two peer-reviewed papers and/or confirmed by two different methods, 113 interactors were revealed for LRRK2, 38 for DAPK1 and 14 for LRRK1, with only a small pool of common interactors between them. Via protein microarray screens however, more interactions were uncovered and the list of overlapping interactors was consequently highly increased. The combination of these two approaches allowed making conclusions about the cellular processes in which ROCO proteins are involved. Cell death was a common theme for all DAPK1 interactors while it was development for LRRK1 and intracellular organization and transport for LRRK2 partners [7]. Indeed, DAPK1 was shown to be involved in cellular processes such as cell death, autophagy, adhesion and inflammatory responses either by phosphorylating downstream targets such as Beclin1 or by direct binding to effector proteins [8,9]. LRRK2 was shown to be involved in a plethora of cellular processes [10,11]. It was demonstrated that lysosomal proteins as well as proteins controlling cytoskeletal functions, translation and vesicular trafficking were affected in kidneys from LRRK2 knock out (KO) mice [12]. LRRK2 phosphorylated a subset of Rab GTPases including Rab10 and Rab12 and was involved in targeting of Rab GTPases to specific membranes, thereby playing a role in intracellular trafficking [13]. Moreover, evidence increases that LRRK2 is also engaged in immune signaling [[14], [15], [16], [17]]. Most importantly, a common pathway regulated by all of the ROCO kinases, is autophagy [[18], [19], [20], [21]]. Autophagy is a basic, internal degradative process, which is one of the major contributors to the catabolic system in every eukaryotic cell. The autophagy pathway is highly conserved and regulated by over 30 genes, which are collectively known as autophagy-related (ATG) genes [22,23]. The main function of autophagy is the maintenance of cellular homeostasis, which is achieved by lysosomal degradation of misfolded or aggregated proteins and of dysfunctional cellular organelles [24,25]. Also, intracellular bacteria or viruses can be removed by autophagy, conferring autophagy a role in cellular self-defense against pathogens [25]. A related, important function of autophagy is the recycling of the degradation products to provide the Cinacalcet HCl receptor with ATP and building blocks for biosynthetic pathways, which is especially relevant in conditions of starvation or hypoxia [26,27]. The fulfillment of such a broad range of functions, including protein quality control, protection of cellular homeostasis and integration of metabolic and immunological signals across cells, sets dysfunctions of autophagy as key factors in the pathology of several diseases including neurodegenerative disorders, cancers and autoimmune syndromes [[28], [29], [30], [31], [32]]. Three different types of autophagy exist – microautophagy, macroautophagy and chaperone-mediated autophagy [33]. Macroautophagy (hereafter called autophagy) is the most recognizable form, which is defined by the presence of cytoplasmic structures, characteristic for each particular step of the process [[34], [35], [36]]. The start of this pathway is marked by the nucleation of a phagophore, usually at a specific compartment of the endoplasmic reticulum (ER). Later, the phagophore surrounds the cytoplasmic content to be degraded and through an elongation process leads to its closure and the emergence of a double-membraned autophagosome that ultimately fuses with a lysosome leading to the formation of autolysosomes in which the cargo is enzymatically degraded [24]. Each of the autophagy steps is driven by specific molecular proteins. In the canonical autophagy, UNC-like kinase 1 (ULK1) is phosphorylated by AMP-activated kinase (AMPK), which is sensitive to intracellular ATP depletion [37]. At the same time, the main autophagy pathway inhibitor, mechanistic target of rapamycin complex 1 (mTORC1) is repressed due to amino acids starvation, what eventually leads to autophagy stimulation [38]. The signal is further transmitted by another protein complex of which VPS34, the class III phosphatidylinositol 3-kinase (PI3K), and Beclin-1 are the main components, which stimulates phagophore nucleation via increase in local phosphatidylinositol 3-phosphate (PI3P) production and activation of effector proteins such as WD repeat domain, phosphoinositide interacting proteins (WIPI) [39]. Finally, the elongation step and the autophagosome formation and closure depend on the presence of microtubule-associated protein 1 light chain 3 (LC3). Due to the conjugation system executed by several ATG proteins, cytosolic LC3-I becomes lipidated with a phosphatidylethanolamine moiety to form LC3-II, which is attached to the extending phagophore and the autophagosome. Detection of LC3-II is therefore considered as a hallmark for the presence of autophagosomes [40].