GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance

Nat Commun. 2013;4:1532. doi: 10.1038/ncomms2540.

Abstract

Efficient engulfment of apoptotic cells is critical for maintaining tissue homoeostasis. When phagocytes recognize 'eat me' signals presented on the surface of apoptotic cells, this subsequently induces cytoskeletal rearrangement of phagocytes for the engulfment through Rac1 activation. However, the intracellular signalling cascades that result in Rac1 activation remain largely unknown. Here we show that G-protein-coupled receptor kinase 6 (GRK6) is involved in apoptotic cell clearance. GRK6 cooperates with GIT1 to activate Rac1, which promotes apoptotic engulfment independently from the two known DOCK180/ELMO/Rac1 and GULP1/Rac1 engulfment pathways. As a consequence, GRK6-deficient mice develop an autoimmune disease. GRK6-deficient mice also have increased iron stores in splenic red pulp in which F4/80(+) macrophages are responsible for senescent red blood cell clearance. Our results reveal previously unrecognized roles for GRK6 in regulating apoptotic engulfment and its fundamental importance in immune and iron homoeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Autoimmune Diseases / blood
  • Autoimmune Diseases / enzymology*
  • Autoimmune Diseases / pathology*
  • Cell Cycle Proteins / metabolism
  • Cellular Senescence
  • Cytoskeletal Proteins / metabolism
  • Electrophoresis, Gel, Two-Dimensional
  • Erythrocytes / metabolism
  • Erythrocytes / pathology
  • Female
  • G-Protein-Coupled Receptor Kinases / deficiency*
  • G-Protein-Coupled Receptor Kinases / metabolism
  • GTPase-Activating Proteins / metabolism
  • Humans
  • Macrophages / metabolism
  • Macrophages / pathology
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microfilament Proteins / metabolism
  • NIH 3T3 Cells
  • Phagocytosis*
  • Phosphorylation
  • Signal Transduction
  • Spleen / metabolism
  • Spleen / pathology
  • rac GTP-Binding Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • GTPase-Activating Proteins
  • Git1 protein, mouse
  • Membrane Proteins
  • Microfilament Proteins
  • moesin
  • radixin
  • G-Protein-Coupled Receptor Kinases
  • G-protein-coupled receptor kinase 6
  • rac GTP-Binding Proteins