Format

Send to

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

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

Author information

1
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065.
2
Laboratory of Signaling and Pathogenesis, Centre National de la Recherche Scientifique, UMR 3691, Institut Pasteur, 75724 Paris, France.
3
Division of Immunology and The Manton Center for Orphan Disease Research, Department of Pathology, Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
4
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR1163; Study Center of Immunodeficiencies, APHP; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, France.
5
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR1163; Study Center of Immunodeficiencies, APHP; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR1163; Study Center of Immunodeficiencies, APHP; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, France.
6
Paris Descartes University, Imagine Institute, 75015 Paris, France.
7
University Medical Centre Freiburg, Centre of Chronic Immunodeficiency, 79098 Freiburg, Germany.
8
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR1163; Study Center of Immunodeficiencies, APHP; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, France.
9
Allergy and Clinical Immunology Unit, Department of Pediatrics, Al-Sabah Hospital, 70459 Kuwait City, Kuwait Department of Pediatrics, Kuwait University, 13110 Kuwait City, Kuwait.
10
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR1163; Study Center of Immunodeficiencies, APHP; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR1163; Study Center of Immunodeficiencies, APHP; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, France Howard Hughes Medical Institute, New York, NY 10065 casanova@rockefeller.edu luigi.notarangelo@childrens.harvard.edu.
11
Division of Immunology and The Manton Center for Orphan Disease Research, Department of Pathology, Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115 Harvard Stem Cell Institute, Harvard University, Boston, MA 02115 casanova@rockefeller.edu luigi.notarangelo@childrens.harvard.edu.

Abstract

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.

PMID:
26008899
PMCID:
PMC4451137
DOI:
10.1084/jem.20141130
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center