Revisiting Rab7 Functions in Mammalian Autophagy: Rab7 Knockout Studies

Abstract

Rab7 (or Ypt7 in yeast) is one of the well-characterized members of the Rab family small GTPases, which serve as master regulators of membrane trafficking in eukaryotes. It localizes to late endosomes and lysosomes and has multiple functions in the autophagic pathway as well as in the endocytic pathway. Because Rab7/Ypt7 has previously been shown to regulate the autophagosome-lysosome fusion step in yeast and fruit flies (i.e., autophagosome accumulation has been observed in both Ypt7-knockout [KO] yeast and Rab7-knockdown fruit flies), it is widely assumed that Rab7 regulates the autophagosome-lysosome fusion step in mammals. A recent analysis of Rab7-KO mammalian cultured cells, however, has revealed that Rab7 is essential for autolysosome maturation (i.e., autolysosome accumulation has been observed in Rab7-KO cells), but not for autophagosome-lysosome fusion, under nutrient-rich conditions. Thus, although Rab7/Ypt7 itself is essential for the proper progression of autophagy in eukaryotes, the function of Rab7/Ypt7 in autophagy in yeast/fruit flies and mammals must be different. In this review article, we describe novel roles of Rab7 in mammalian autophagy and discuss its functional diversification during evolution.

Autophagy and cardiac aging

“…A recent study demonstrated that ULK1 regulates not only the initiation step but also fusion with lysosome [31]. For further details regarding the molecular basis of autophagosome and autophagolysosome formation, please refer to previous review articles [30,32,33].…”

“…Mechanistically, Sirt1 deacetylates and activates FoxO family transcription factors (Fig. 3), thereby facilitating autophagy through upregulation of Atg genes and Rab7 [74,75,93], a regulator of autophagosome and autophagolysosome maturation [32,33]. Sirt1 localizes in the nucleus, as well as the cytoplasm, and cytosolic Sirt1 can also increase autophagy [91].…”

Enhanced autophagic retrograde axonal transport by dynein intermediate chain upregulation improves Aβ clearance and cognitive function in APP/PS1 double transgenic mice

“…Other adaptor proteins selectively promote or inhibit autophagosome transport and autophagosome-lysosome maturation through direct binding to kinesin and dynein [11]. Of these proteins, Rab7 is a vesicular transportrelated protein that promotes the fusion of autophagosomes and lysosomes by regulating their movement on the microtubules [12,13]. Rab7 binds to oxysterol-binding protein-related protein 1L (ORP1L), and then connects to dynein-dynactin [13].…”

The RBG-1–RBG-2 complex modulates autophagy activity by regulating lysosomal biogenesis and function in C. elegans

“…Depletion of the RAB7 GAP Armus impairs autolysosome formation and acidification (Carroll et al, 2013). RAB7 knockout cells show accumulation of autolysosomes, indicating that RAB7 is essential for autolysosome maturation (Kuchitsu and Fukuda, 2018). In EPG5-depleted cells or epg-5 mutant animals, GFP::RAB7 forms abnormally enlarged punctate structures .…”