iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS

Science. 2012 Jan 13;335(6065):229-32. doi: 10.1126/science.1214448.

Abstract

Innate immune responses are vital for pathogen defense but can result in septic shock when excessive. A key mediator of septic shock is tumor necrosis factor-α (TNFα), which is shed from the plasma membrane after cleavage by the TNFα convertase (TACE). We report that the rhomboid family member iRhom2 interacted with TACE and regulated TNFα shedding. iRhom2 was critical for TACE maturation and trafficking to the cell surface in hematopoietic cells. Gene-targeted iRhom2-deficient mice showed reduced serum TNFα in response to lipopolysaccharide (LPS) and could survive a lethal LPS dose. Furthermore, iRhom2-deficient mice failed to control the replication of Listeria monocytogenes. Our study has identified iRhom2 as a regulator of innate immunity that may be an important target for modulating sepsis and pathogen defense.

Publication types

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

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism*
  • ADAM17 Protein
  • Amino Acid Sequence
  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Base Sequence
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cell Membrane / metabolism
  • Gene Deletion
  • Immunity, Innate*
  • Lipopolysaccharides / immunology*
  • Listeria monocytogenes / immunology
  • Listeria monocytogenes / physiology
  • Listeriosis / immunology*
  • Listeriosis / metabolism
  • Listeriosis / microbiology
  • Listeriosis / pathology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism
  • Macrophages, Peritoneal / microbiology
  • Mice
  • Molecular Sequence Data
  • Protein Transport
  • Shock, Septic / immunology*
  • Shock, Septic / metabolism
  • Spleen / cytology
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Carrier Proteins
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • iRhom2 protein, mouse
  • ADAM Proteins
  • ADAM17 Protein
  • Adam17 protein, mouse