Arf-like GTPase Arl8: Moving from the periphery to the center of lysosomal biology - PubMed (original) (raw)

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Arf-like GTPase Arl8: Moving from the periphery to the center of lysosomal biology

Divya Khatter et al. Cell Logist. 2015.

Abstract

Lysosomes are dynamic organelles that not only mediate degradation of cellular substrates but also play critical roles in processes such as cholesterol homeostasis, plasma membrane repair, antigen presentation, and cell migration. The small GTPase Arl8, a member of Arf-like (Arl) family of proteins, has recently emerged as a crucial regulator of lysosome positioning and membrane trafficking toward lysosomes. Through interaction with its effector SKIP, the human Arl8 paralog (Arl8b) mediates kinesin-1 dependent motility of lysosomes on microtubule tracks toward the cell periphery. Arl8b-mediated kinesin-driven motility is also implicated in regulating lytic granule polarization in NK cells, lysosome tubulation in macrophages, cell spreading, and migration. Moreover, Arl8b regulates membrane traffic toward lysosomes by recruiting subunits of the HOPS complex, a multi-subunit tethering complex that mediates endo-lysosome fusion. Here we provide a brief review on this recently characterized lysosomal GTPase and summarize the studies focusing on its known functions in regulating lysosomal motility and delivery of endocytic cargo to the lysosomes. We also explore the role of human Arl8b and its orthologs upon infection by intracellular pathogens.

Keywords: Arf-like GTPase; Arl8; BORC; HOPS; Motors; SKIP; autophagy; late endosome; lysosome; membrane trafficking.

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Figures

Figure 1.

Figure 1.

Conservation of Arl8 protein across species. Arl8 is a primitive GTPase which is highly conserved from protozoans to metazoans as well in plants. Multiple sequence alignment was constructed using CLC sequence viewer software and NCBI accession numbers of the protein sequences used for sequence comparison were as follows: Homo sapiens (man) Arl8a, NP_620150.1; Homo sapiens (man) Arl8b, NP_060654.1; Pan troglodytes (chimpanzee), XP_001142369.1; Canis lupus familiaris (dog), XP_853013.1; Bos taurus (cattle), NP_001039536.1; Gallus gallus (chicken), XP_414440.3; Mus musculus (mouse), NP_080287.1; Rattus norvegicus (rat), NP_001019503.1; Xenopus tropicalis (frog), NP_001190182.1; Danio rerio (zebrafish), XP_002663861.1; Caenorhabditis elegans (worm), NP_502791.1; Drosophila melanogaster (fruit fly), NP_649769.1; Arabidopsis thaliana (small flowering plant), NP_568553.1; and Oryza sativa (rice plant), NP_001048027.1.

Figure 2.

Figure 2.

Human Arl8 paralogs (Arl8a and Arl8b) localize to lysosomes. HeLa cells were transfected with either Arl8a-Myc-Flag (A) or Arl8b-HA (B) and analyzed for lysosomal localization by confocal microscopy. The figure indicates the peripheral recruitment of LAMP1-positive endosomes (red) in Arl8a/b transfected cells (green). Colocalized pixels are represented in the inset. Scale bar: 10 μm.

Figure 3.

Figure 3.

Human Arl8b governs the distribution of lysosomes in mammalian cells. Control (A), Arl8b-silenced (B), and Arl8b-overexpressing (C) HeLa cells were transfected with GFP-LAMP1 and costained with antibodies to α-tubulin (blue) to label microtubules and pericentrin (red) to label MTOC. Knockdown of Arl8b results in lysosomal clustering at MTOC while its overexpression distributes lysosomes to the cell periphery. Scale bar: 10 μm.

Figure 4.

Figure 4.

A model depicting the interplay of transport and fusion machinery operating at endosome-lysosome junction. Small GTPase Arl8b is recruited to lysosomal membranes by multi-subunit complex BORC. GTP-bound Arl8b interacts with its effectors: SKIP to mediate kinesin-dependent anterograde lysosomal movement and HOPS to accomplish vesicle (late endosome/phagosome) fusion at lysosomes.

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