Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia

J Exp Med. 2015 Jun 1;212(6):939-51. doi: 10.1084/jem.20141130. Epub 2015 May 25.


Inherited, complete deficiency of human HOIL-1, a component of the linear ubiquitination chain assembly complex (LUBAC), underlies autoinflammation, infections, and amylopectinosis. We report the clinical description and molecular analysis of a novel inherited disorder of the human LUBAC complex. A patient with multiorgan autoinflammation, combined immunodeficiency, subclinical amylopectinosis, and systemic lymphangiectasia, is homozygous for a mutation in HOIP, the gene encoding the catalytic component of LUBAC. The missense allele (L72P, in the PUB domain) is at least severely hypomorphic, as it impairs HOIP expression and destabilizes the whole LUBAC complex. Linear ubiquitination and NF-κB activation are impaired in the patient's fibroblasts stimulated by IL-1β or TNF. In contrast, the patient's monocytes respond to IL-1β more vigorously than control monocytes. However, the activation and differentiation of the patient's B cells are impaired in response to CD40 engagement. These cellular and clinical phenotypes largely overlap those of HOIL-1-deficient patients. Clinical differences between HOIL-1- and HOIP-mutated patients may result from differences between the mutations, the loci, or other factors. Our findings show that human HOIP is essential for the assembly and function of LUBAC and for various processes governing inflammation and immunity in both hematopoietic and nonhematopoietic cells.

Publication types

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

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • CD40 Ligand / metabolism
  • Catalysis
  • Female
  • Fibroblasts / metabolism
  • Gene Expression Regulation*
  • Genetic Complementation Test
  • Germ-Line Mutation
  • Glycogen Storage Disease Type IV / pathology
  • Homozygote
  • Humans
  • Immunologic Deficiency Syndromes / pathology
  • Inflammation
  • Lymphangiectasis / pathology
  • Monocytes / metabolism
  • Mutation, Missense
  • NF-kappa B / metabolism
  • Sequence Homology, Amino Acid
  • Transcription Factors
  • Ubiquitin / chemistry
  • Ubiquitin-Protein Ligases / deficiency*
  • Ubiquitin-Protein Ligases / genetics
  • Young Adult


  • NF-kappa B
  • Transcription Factors
  • Ubiquitin
  • CD40 Ligand
  • RBCK1 protein, human
  • RNF31 protein, human
  • Ubiquitin-Protein Ligases