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mTOR controls lysosome tubulation and antigen presentation in macrophages and dendritic cells

Amra Saric1, Victoria E B Hipolito1, Jason G Kay2

  • 1Molecular Science Program and Department of Chemistry and Biology, Ryerson University, Toronto, ON M5B 2K3, Canada.

Molecular Biology of the Cell
|November 20, 2015
PubMed

Insights

Lipopolysaccharide (LPS) triggers a signaling pathway involving mTOR, which is crucial for lysosome tubulation and major histocompatibility complex II secretion in immune cells. This discovery highlights mTOR

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Macrophages and dendritic cells undergo lysosome remodeling upon lipopolysaccharide (LPS) exposure, transitioning from punctate structures to tubules.
  • Tubular lysosomes are associated with critical cellular functions including phagosome maturation, fluid retention, and antigen presentation.
  • Lysosomes are increasingly recognized as cellular sensors of stress and metabolic status, particularly through the mechanistic target of rapamycin (mTOR) kinase.

Purpose of the Study:

  • To investigate the role of mTOR in lipopolysaccharide (LPS)-induced lysosome tubulation and major histocompatibility complex II (MHC II) secretion.
  • To elucidate the signaling pathways regulating LPS-induced lysosome morphology changes in immune cells.
  • To explore the connection between mTOR, lysosome trafficking, and cytoskeletal motor proteins.

Main Methods:

  • Stimulation of macrophages and dendritic cells with LPS.
  • Analysis of lysosome morphology using microscopy.
  • Assessment of mTOR signaling pathway activation.
  • Investigation of the role of Arl8b, a lysosomal GTPase, and kinesin motor proteins.
  • Pharmacological inhibition of mTOR activity.

Main Results:

  • LPS exposure stimulates mTOR signaling in macrophages and dendritic cells.
  • mTOR activation is essential for LPS-induced lysosome tubulation and MHC II secretion.
  • The phosphatidylinositol 3-kinase-Akt-mTOR pathway regulates lysosome tubulation independently of IRAK1/4 and TBK signaling.
  • LPS treatment increases membrane-associated Arl8b levels in an mTOR-dependent manner, promoting kinesin-driven lysosome movement.
  • mTOR inhibition blocks outward lysosome movement.

Conclusions:

  • mTOR is a key regulator of LPS-induced lysosome tubulation and trafficking in leukocytes.
  • mTOR signaling interfaces with the Arl8b-kinesin machinery to control lysosome morphology and movement.
  • These findings reveal a novel mechanism by which immune cells modulate lysosome function in response to external stimuli.

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