Tubular lysosomes harbor active ion gradients and poise macrophages for phagocytosis

Proc Natl Acad Sci U S A. 2021 Oct 12;118(41):e2113174118. doi: 10.1073/pnas.2113174118.


Lysosomes adopt dynamic, tubular states that regulate antigen presentation, phagosome resolution, and autophagy. Tubular lysosomes are studied either by inducing autophagy or by activating immune cells, both of which lead to cell states where lysosomal gene expression differs from the resting state. Therefore, it has been challenging to pinpoint the biochemical properties lysosomes acquire upon tubulation that could drive their functionality. Here we describe a DNA-based assembly that tubulates lysosomes in macrophages without activating them. Proteolytic activity maps at single-lysosome resolution revealed that tubular lysosomes were less degradative and showed proximal to distal luminal pH and Ca2+ gradients. Such gradients had been predicted but never previously observed. We identify a role for tubular lysosomes in promoting phagocytosis and activating MMP9. The ability to tubulate lysosomes without starving or activating immune cells may help reveal new roles for tubular lysosomes.

Keywords: DNA nanotechnology; MMP9; lysosomes; macrophages; phagocytosis.

Publication types

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

MeSH terms

  • Animals
  • Aptamers, Nucleotide / pharmacology
  • Autophagy / physiology
  • COS Cells
  • Calcium / metabolism
  • Carbocyanines / pharmacology
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • DNA / chemistry*
  • Hep G2 Cells
  • Humans
  • Lysosomes / drug effects
  • Lysosomes / metabolism*
  • Macrophages / immunology*
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Nanocomposites / chemistry
  • Phagocytosis / physiology*
  • Phagosomes / metabolism
  • RAW 264.7 Cells


  • Aptamers, Nucleotide
  • Carbocyanines
  • Tudor
  • DNA
  • Matrix Metalloproteinase 9
  • Calcium