Role of linear ubiquitination in health and disease

Patricia Brazee, Laura A. Dada, Jacob I. Sznajder*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

8 Scopus citations

Abstract

The covalent attachment of ubiquitin to targetproteins is one of themost prevalent post-translational modifications, regulating a myriad of cellular processes including cell growth, survival, and metabolism. Recently, a novel RING E3 ligase complex was described, called linear ubiquitin assembly complex (LUBAC), which is capable of connecting ubiquitin molecules in a novel head-to-tail fashion via the N-terminal methionine residue. LUBAC is a heteromeric complex composed of heme-oxidized iron-responsive element-binding protein 2 ubiquitin ligase-1L (HOIL-1L), HOIL-1L-interacting protein, and shankassociated RH domain-interacting protein (SHARPIN). The essential role of LUBAC-generated linear chains for activation of nuclear factorkB (NF-κB) signaling was first described in the activation of tumor necrosis factor-a receptor signaling complex. A decade of research has identified additional pathways that use LUBAC for downstream signaling, including CD40 ligand and the IL-1b receptor, as well as cytosolic pattern recognition receptors including nucleotide-binding oligomerization domain containing 2 (NOD2), retinoic acid-inducible gene 1 (RIG-1), and the NOD-like receptor family, pyrin domain containing 3 inflammasome (NLRP3). Even though the three components of the complex are required for full activation of NF-κB, the individual components of LUBAC regulate specific cell type- and stimuli-dependent effects. In humans, autosomal defects in LUBAC are associated with both autoinflammation and immunodeficiency, with additional disorders described in mice. Moreover, in the lung epithelium, HOIL-1L ubiquitinates target proteins independently of the other LUBAC components, adding another layer of complexity to the function and regulation of LUBAC. Althoughmany advances have been made, the diverse functions of linear ubiquitin chains and the regulationofLUBACarenot yet completelyunderstood. Inthis review, we discuss the various roles of linear ubiquitin chains and point to areas of study that would benefit from further investigation into LUBACmediated signaling pathways in lung pathophysiology.

Original languageEnglish (US)
Pages (from-to)761-768
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume54
Issue number6
DOIs
StatePublished - Jun 2016

Keywords

  • Inflammation
  • LUBAC
  • Nondegradative ubiquitination

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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