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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Bacterial Infections / genetics
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Bacterial Infections / immunology
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Cell Cycle Proteins / genetics
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Cell Line
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Fibroblasts / immunology
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Fibroblasts / metabolism
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Glycogen Storage Disease Type IV / genetics*
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Hereditary Autoinflammatory Diseases / genetics*
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Humans
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Immunologic Deficiency Syndromes / genetics*
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Immunologic Deficiency Syndromes / metabolism
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Interleukin-1beta / metabolism
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Monocytes / immunology
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Monocytes / metabolism
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NF-kappa B / metabolism*
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Oligonucleotide Array Sequence Analysis
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Repressor Proteins / genetics
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Transcription Factors
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Ubiquitin-Protein Ligases / deficiency
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Ubiquitin-Protein Ligases / genetics*
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Ubiquitin-Protein Ligases / metabolism
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Ubiquitination
Substances
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Cell Cycle Proteins
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Interleukin-1beta
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NF-kappa B
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Repressor Proteins
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TRIB3 protein, human
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Transcription Factors
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RBCK1 protein, human
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Ubiquitin-Protein Ligases
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Protein Serine-Threonine Kinases