Blood Journal
Leading the way in experimental and clinical research in hematology

Plant homologue constitutive photomorphogenesis 9 (COP9) signalosome subunit CSN5 regulates innate immune responses in macrophages

  1. Zhongbin Deng1,
  2. Ruggero Pardi2,
  3. William Cheadle3,
  4. Xiaoyu Xiang1,
  5. Shuangyin Zhang4,
  6. Spandan V. Shah4,
  7. William Grizzle5,
  8. Donald Miller1,
  9. John Mountz4, and
  10. Huang-Ge Zhang1,3
  1. 1James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville, Louisville, KY;
  2. 2Vita-Salute San Raffaele University School of Medicine, Milan, Italy;
  3. 3Robley Rex Veterans Health Administration Medical Center, Louisville, KY; and
  4. 4Division of Clinical Immunology and Rheumatology, Department of Medicine, and
  5. 5Department of Pathology, University of Alabama at Birmingham, Birmingham, AL

Abstract

COP9 plays a role in plant innate immunity. The role of COP9 in mammalian innate immune responses is unknown. Here, we show that the COP9 signalosome subunit 5 (CSN5) is required for activation of proinflammatory kinases p38 and Erk and for down-regulation of the expression of genes regulated by nuclear factor E2-related factor 2. Mice with myeloid-specific CSN5 deficiency have lower mortality in polymicrobial sepsis. CSN5 is required for both Toll-like receptor (TLR) and reactive oxygen species–mediated deneddylation of Cul3, which is essential for Cul3/Keap1-mediated degradation of nuclear factor E2-related factor 2. On the basis of our results COP9 subunit CSN5 is considered to be an essential component of mammalian innate immunity.

  • Submitted October 20, 2010.
  • Accepted February 7, 2011.
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