SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex

Nature. 2011 Mar 31;471(7340):633-6. doi: 10.1038/nature09815.


Cpdm (chronic proliferative dermatitis) mice develop chronic dermatitis and an immunodeficiency with increased serum IgM, symptoms that resemble those of patients with X-linked hyper-IgM syndrome and hypohydrotic ectodermal dysplasia (XHM-ED), which is caused by mutations in NEMO (NF-κB essential modulator; also known as IKBKG). Spontaneous null mutations in the Sharpin (SHANK-associated RH domain interacting protein in postsynaptic density) gene are responsible for the cpdm phenotype in mice. SHARPIN shows significant similarity to HOIL-1L (also known as RBCK1), a component of linear ubiquitin chain assembly complex (LUBAC), which induces NF-κB activation through conjugation of linear polyubiquitin chains to NEMO. Here, we identify SHARPIN as an additional component of LUBAC. SHARPIN-containing complexes can linearly ubiquitinate NEMO and activated NF-κB. Thus, we re-define LUBAC as a complex containing SHARPIN, HOIL-1L, and HOIP (also known as RNF31). Deletion of SHARPIN drastically reduced the amount of LUBAC, which resulted in attenuated TNF-α- and CD40-mediated activation of NF-κB in mouse embryonic fibroblasts (MEFs) or B cells from cpdm mice. Considering the pleomorphic phenotype of cpdm mice, these results confirm the predicted role of LUBAC-mediated linear polyubiquitination in NF-κB activation induced by various stimuli, and strongly suggest the involvement of LUBAC-induced NF-κB activation in various disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD40 Ligand / metabolism
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / metabolism*
  • NF-kappa B / metabolism*
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligase Complexes / chemistry
  • Ubiquitin-Protein Ligase Complexes / metabolism
  • Ubiquitin-Protein Ligases / metabolism


  • Carrier Proteins
  • HOIL-1L protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • NEMO protein, mouse
  • NF-kappa B
  • Nerve Tissue Proteins
  • Tumor Necrosis Factor-alpha
  • Ubiquitin
  • sharpin
  • CD40 Ligand
  • Ubiquitin-Protein Ligase Complexes
  • Rnf31 protein, mouse
  • Ubiquitin-Protein Ligases