Roles of linear ubiquitinylation, a crucial regulator of NF-κB and cell death, in the immune system.

Abstract

Linear ubiquitinylation, a newly identified post-translational modification, is catalyzed by the linear ubiquitin assembly complex (LUBAC), which is composed of three different subunits, HOIL-1L (heme-oxidized IRP2 ligase 1L), HOIP (HOIL-1 interacting protein), and SHARPIN (SHANK-associated RH domain-interacting protein). LUBAC plays a critical role in the activation of nuclear factor-κB (NF-κB) signaling triggered by a variety of stimuli, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and pathogen-derived components, and in the protection from cell death. Loss of function of SHARPIN in mice triggers chronic inflammation in multiple organs including the skin, as well as immunodeficiency. In humans, mutations in the gene encoding HOIL-1L cause chronic hyperinflammation and immunodeficiency, which are both associated with decreased levels of LUBAC. The linear ubiquitinylation activity of LUBAC is indispensable for B-cell function in mice, and hyperactivation of LUBAC is associated with oncogenesis in certain forms of B-cell lymphoma. In this review, the current understanding of the biochemistry of LUBAC-mediated linear ubiquitinylation and its involvement in the immune system are discussed.

• Authors: Katsuhiro Sasaki, Kazuhiro Iwai
• Journal: Immunological reviews (Immunol Rev) Vol. 266 Issue 1 Pg. 175-89 (Jul 2015) ISSN: 1600-065X [Electronic] England
• PMID: 26085215 (Publication Type: Journal Article, Review)
• Copyright: © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Carrier Proteins
• HOIL-1L protein, mouse
• Multiprotein Complexes
• NF-kappa B
• Nerve Tissue Proteins
• sharpin
• RNF31 protein, human
• Ubiquitin-Protein Ligases

Topics

• Animals
• B-Lymphocytes (immunology)
• Carcinogenesis
• Carrier Proteins (genetics, metabolism)
• Cell Death
• Humans
• Immune System
• Multiprotein Complexes
• Mutation (genetics)
• NF-kappa B (metabolism)
• Nerve Tissue Proteins (metabolism)
• Signal Transduction
• Ubiquitin-Protein Ligases (metabolism)
• Ubiquitination