title: Lysosomal trafficking, antigen presentation, and microbial killing are controlled by the Arf-like GTPase Arl8b.
abstract: Antigen presentation and microbial killing are critical arms of host defense that depend upon cargo trafficking into lysosomes. Yet, the molecular regulators of traffic into lysosomes are only partly understood. Here, using a lysosome-dependent immunological screen of a trafficking shRNA library, we identified the Arf-like GTPase Arl8b as a critical regulator of cargo delivery to lysosomes. Homotypic fusion and vacuole protein sorting (HOPS) complex members were identified as effectors of Arl8b and were dependent on Arl8b for recruitment to lysosomes, suggesting that Arl8b-HOPS plays a general role in directing traffic to lysosomes. Moreover, the formation of CD1 antigen-presenting complexes in lysosomes, their delivery to the plasma membrane, and phagosome-lysosome fusion were all markedly impaired in Arl8b silenced cells resulting in corresponding defects in T cell activation and microbial killing. Together, these results define Arl8b as a key regulator of lysosomal cellular and immunological functions.
authors.affiliation: Harvard Division of Medical Sciences, Graduate Program in Immunology and Harvard-MIT MD PhD Program, Boston, MA 02115, USA.
authors.forename: Salil
authors.initials: S
authors.lastname: Garg
authors.forename: Mahak
authors.initials: M
authors.lastname: Sharma
authors.forename: Cindy
authors.initials: C
authors.lastname: Ung
authors.forename: Amit
authors.initials: A
authors.lastname: Tuli
authors.forename: Duarte C
authors.initials: DC
authors.lastname: Barral
authors.forename: David L
authors.initials: DL
authors.lastname: Hava
authors.forename: Natacha
authors.initials: N
authors.lastname: Veerapen
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.forename: Michael B
authors.initials: MB
authors.lastname: Brenner
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017951:Antigen Presentation / Q000235:genetics; D000941:Antigens / Q000276:immunology / Q000378:metabolism*; D055610:Antigens, CD1d / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism*; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D011510:Proteolipids / Q000276:immunology / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: C511801:ARL8B protein, human; D000941:Antigens; D055610:Antigens, CD1d; D016207:Cytokines; D011510:Proteolipids; D034741:RNA, Small Interfering; C549959:VPS41 protein, human; D033921:Vesicular Transport Proteins; D000090802:rab7 GTP-Binding Proteins; D020727:ADP-Ribosylation Factors; D020691:rab GTP-Binding Proteins