Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency

Nat Immunol. 2012 Dec;13(12):1178-86. doi: 10.1038/ni.2457. Epub 2012 Oct 28.

Abstract

We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic autoinflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1 (RBCK1), a component of the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-κB activation in response to interleukin 1β (IL-1β) was compromised in the patients' fibroblasts. By contrast, the patients' mononuclear leukocytes, particularly monocytes, were hyper-responsive to IL-1β. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1β responses thus differed between cell types, consistent with the unique association of autoinflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-κB-dependent IL-1β responses differently in different cell types.

Publication types

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

MeSH terms

  • Bacterial Infections / genetics
  • Bacterial Infections / immunology
  • Cell Cycle Proteins / genetics
  • Cell Line
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Glycogen Storage Disease Type IV / genetics*
  • Hereditary Autoinflammatory Diseases / genetics*
  • Humans
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / metabolism
  • Interleukin-1beta / metabolism
  • Monocytes / immunology
  • Monocytes / metabolism
  • NF-kappa B / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Repressor Proteins / genetics
  • Transcription Factors
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination

Substances

  • Cell Cycle Proteins
  • Interleukin-1beta
  • NF-kappa B
  • Repressor Proteins
  • TRIB3 protein, human
  • Transcription Factors
  • RBCK1 protein, human
  • Ubiquitin-Protein Ligases
  • Protein-Serine-Threonine Kinases

Associated data

  • GEO/GSE40752