Lysosomal trafficking, antigen presentation, and microbial killing are controlled by the Arf-like GTPase Arl8b

Immunity. 2011 Aug 26;35(2):182-93. doi: 10.1016/j.immuni.2011.06.009. Epub 2011 Jul 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / genetics
  • ADP-Ribosylation Factors / immunology
  • ADP-Ribosylation Factors / metabolism*
  • Antigen Presentation / genetics
  • Antigens / immunology
  • Antigens / metabolism*
  • Antigens, CD1d / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic / genetics
  • HeLa Cells
  • Humans
  • Lymphocyte Activation / genetics
  • Lysosomes / metabolism*
  • Natural Killer T-Cells / immunology
  • Natural Killer T-Cells / metabolism*
  • Natural Killer T-Cells / pathology
  • Protein Binding / genetics
  • Protein Transport / genetics
  • Proteolipids / immunology
  • Proteolipids / metabolism*
  • RNA, Small Interfering / genetics
  • Vesicular Transport Proteins / metabolism
  • rab GTP-Binding Proteins / metabolism

Substances

  • ARL8B protein, human
  • Antigens
  • Antigens, CD1d
  • Cytokines
  • Proteolipids
  • RNA, Small Interfering
  • VPS41 protein, human
  • Vesicular Transport Proteins
  • rab7 protein
  • ADP-Ribosylation Factors
  • rab GTP-Binding Proteins