Arf-like GTPase Arl8b regulates lytic granule polarization and natural killer cell–mediated cytotoxicity

Abstract

By exploiting NK cell LROs (known as lytic granules) as a model, a new role is defined for Arl8b in regulating motility and exocytosis of lytic granules of NK cells. Not only lytic granules but also the MTOC is unable to polarize toward the immune synapse formed between the NK cell and its target in Arl8b-depleted NK cells.

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

“…40 Unlike in melanocytes, Arl8b localized to the LROs/lytic granules in Natural Killer (NK) cells, and along with SKIP and kinesin-1 was required for the polarized secretion of lytic granules toward the immune synapse, leading to NK cell-mediated cytotoxicity. 41 Arl8b and SKIP were also found to mediate kinesin-driven lysosome tubulation in lipopolysaccharide-treated macrophages, which facilitates retention of fluid-phase endocytic content as well as phagosomes maturation and acidification in activated macrophages. 22,42 A recent study has also elucidated roles for Arl8b and kinesin-1 in cell migration by mediating anterograde transport of the late endosomal protein complex p14-MP1 (MAPK/ERK kinase 1 partner MP1, and its endosomal adaptor protein p14) to focal adhesions, leading to their disassembly and turnover.…”

“…41 Acting along with kinesin KIF1A, Arl8b also regulates the transport of synaptic vesicles in C. elegans. 21,44 As several diseases arise from defects in the biogenesis and function LROs, it will be important in the future to explore the potential role of Arl8 in transport of LROs and their exocytosis.…”

MHC Class II Presentation Is Controlled by the Lysosomal Small GTPase, Arl8b

“…The small GTPase Arl8b colocalizes to MHC II + compartments and to lysosomes Arl8b has previously been shown to localize to lysosomes and lysosome-related organelles in mouse and human cells (21,23). Because MHC II is enriched in lysosomes, we asked whether Arl8b localized in lysosomes and MHC II + compartments in DCs.…”

“…Interestingly, depending on the effectors it recruits, Arl8b can be involved in both cargo delivery to and motility of lysosomes. For example, Arl8b was shown to control the outward movement of lysosomes and lysosome-related organelles such as lytic granules in NK cells by recruiting SifA and kinesininteracting protein that, in turn, binds to the kinesin motor Kif5b (22,23). Recent studies also suggested that Arl8b plays a role in lysosomal tubulation in macrophages and in Salmonellainfected cells, a process that requires the recruitment of kinesin motors (24,25).…”

Negative Regulation of Melanoma Differentiation-associated Gene 5 (MDA5)-dependent Antiviral Innate Immune Responses by Arf-like Protein 5B

“…For instance, Arl16 negatively regulates RIG-I-mediated signaling by interacting with the C-terminal repressor domain of RIG-I (21). Arl8B is required for the polarization of lytic granules toward the immune synapse in natural killer cells and their cytotoxicity (28).…”