Abstract
The small GTPase, Rab7a, and the regulators of its GDP/GTP-binding status were shown to have roles in both endocytic membrane traffic and autophagy. Classically known to regulate endosomal retrograde transport and late endosome-lysosome fusion, earlier work has indicated a role for Rab7a in autophagosome-lysosome fusion as well as autolysosome maturation. However, as suggested by recent findings on PTEN-induced kinase 1 (PINK1)-Parkin-mediated mitophagy, Rab7a and its regulators are critical for the correct targeting of Atg9a-bearing vesicles to effect autophagosome formation around damaged mitochondria. This mitophagosome formation role for Rab7a is dependent on an intact Rab cycling process mediated by the Rab7a-specific guanine nucleotide exchange factor (GEF) and GTPase activating proteins (GAPs). Rab7a activity in this regard is also dependent on the retromer complex, as well as phosphorylation by the TRAF family-associated NF-κB activator binding kinase 1 (TBK1). Here, we discuss these recent findings and broadened perspectives on the role of the Rab7a network in PINK1-Parkin mediated mitophagy.
Highlights
Macroautophagy is a conserved cellular process in eukaryotes that involves membrane remodeling for the degradation and recycling of cellular components, be it soluble cytosolic components, cytoplasmic aggregates, or membranous organelles.The process begins with the formation of a double-membraned autophagosome [1], whose content is eventually degraded via fusion with the lysosome [2]
Autophagosome formation and maturation are primarily dependent on the action of several protein complexes, components of which were first genetically defined in S. cerevisiae as a large set of autophagy (Atg) genes, most of which have conserved orthologues in mammals
The Unc51-like kinase 1 (ULK1)/Atg1-containing complex is the upstream component of physiological autophagy signaling, taking cues from the nutrient-sensing and stress response pathways regulated by the molecular target of rapamycin complex 1 and liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK)
Summary
Macroautophagy (or commonly abbreviated as ‘autophagy’) is a conserved cellular process in eukaryotes that involves membrane remodeling for the degradation and recycling of cellular components, be it soluble cytosolic components, cytoplasmic aggregates, or membranous organelles. ULK1 phosphorylates Beclin1/Atg and activates the second complex containing Beclin and the phosphatidylinositol 3-kinase Vps34 [3], whose activity results in localized production of phosphatidylinositol (3,4,5)-trisphosphate The latter serves as a docking platform for the recruitment of components required for the formation of an autophagy specific initiating structure known as the phagophore or the isolation membrane (IM), such as the WD-repeat protein interacting with phosphoinositides (WIPI) family members/Atg18 [4]. Autophagosome-lysosome fusion is critically dependent on specific soluble NSF attachment protein receptors (SNAREs) [28], the autophagosome targeted syntaxin 17 (Stx17) [29], as well as longin SNARE Ykt6 [30,31,32,33,34] In this regard, multiple members of the Rab family of small GTPases, with classical roles in exocytic and endocytic membrane trafficking, are known to be important or critical for autophagy [35,36,37]. These works and the new perspectives formed are discussed in the paragraphs below
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