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

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.

SUBMITTER: Khatter D

PROVIDER: S-EPMC4820812 | biostudies-literature | 2015 Jul-Sep

REPOSITORIES: biostudies-literature

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

Khatter Divya D Sindhwani Aastha A Sharma Mahak M

Cellular logistics 20150701 3

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 kine ...[more]

PMID: 27057420

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Project description:In eukaryotes, GTP-bound ARF GTPases promote intracellular membrane traffic by mediating the recruitment of coat proteins, which in turn sort cargo proteins into the forming membrane vesicles. Mammals employ several classes of ARF GTPases which are activated by different ARF guanine-nucleotide exchange factors (ARF-GEFs). In contrast, flowering plants only encode evolutionarily conserved ARF1 GTPases (class I) but not the other classes II and III known from mammals, as suggested by phylogenetic analysis of ARF family members across the five major clades of eukaryotes. Instead, flowering plants express plant-specific putative ARF GTPases such as ARFA and ARFB, in addition to evolutionarily conserved ARF-LIKE (ARL) proteins. Here we show that all eight ARF-GEFs of Arabidopsis interact with the same ARF1 GTPase, whereas only a subset of post-Golgi ARF-GEFs also interacts with ARFA, as assayed by immunoprecipitation. Both ARF1 and ARFA were detected at the Golgi stacks and the trans-Golgi network (TGN) by both live-imaging with the confocal microscope and nano-gold labeling followed by EM analysis. ARFB representing another plant-specific putative ARF GTPase was detected at both the plasma membrane and the TGN. The activation-impaired form (T31N) of ARF1, but neither ARFA nor ARFB, interfered with development, although ARFA-T31N interfered, like ARF1-T31N, with the GDP-GTP exchange. Mutant plants lacking both ARFA and ARFB transcripts were viable, suggesting that ARF1 is sufficient for all essential trafficking pathways under laboratory conditions. Detailed imaging of molecular markers revealed that ARF1 mediated all known trafficking pathways whereas ARFA was not essential to any major pathway. In contrast, the hydrolysis-impaired form (Q71L) of both ARF1 and ARFA, but not ARFB, had deleterious effects on development and various trafficking pathways. However, the deleterious effects of ARFA-Q71L were abolished by ARFA-T31N inhibiting cognate ARF-GEFs, both in cis (ARFA-T31N,Q71L) and in trans (ARFA-T31N + ARFA-Q71L), suggesting indirect effects of ARFA-Q71L on ARF1-mediated trafficking. The deleterious effects of ARFA-Q71L were also suppressed by strong over-expression of ARF1, which was consistent with a subset of BIG1-4 ARF-GEFs interacting with both ARF1 and ARFA. Indeed, the SEC7 domain of BIG5 activated both ARF1 and ARFA whereas the SEC7 domain of BIG3 only activated ARF1. Furthermore, ARFA-T31N impaired root growth if ARF1-specific BIG3 was knocked out and only ARF1- and ARFA-activating BIG4 was functional. Activated ARF1 recruits different coat proteins to different endomembrane compartments, depending on its activation by different ARF-GEFs. Unlike ARF GTPases, ARF-GEFs not only localize at distinct compartments but also regulate specific trafficking pathways, suggesting that ARF-GEFs might play specific roles in traffic regulation beyond the activation of ARF1 by GDP-GTP exchange.

Dataset Information

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

Publications

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

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