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Transcriptional analysis of whole blood and PBMCs from human HOIP deficiency patients

ABSTRACT: LUBAC (linear ubiquitin assembly complex) consists of HOIP, HOIL1 and SHARPIN. HOIP deficiency has been characterized by immunodeficiency, autoinflammation and amylopectinosis. To explore the molecular mechanism of the autoinflammation, we performed a transcriptome-wide analysis using whole blood and unstimulated PBMCs of a HOIP deficiency patient.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118901 | GEO | 2018/08/23

REPOSITORIES: GEO

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Transcriptomic profiling of human SHARPIN deficiency

Project description:The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN, and is essential for proper immune responses. Patients with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage. In mice, the loss of Sharpin leads to severe dermatitis due to excessive cell death in keratinocytes. Here we report two patients with SHARPIN deficiency manifesting autoinflammatory symptoms but unexpectedly, no dermatologic manifestations. Patient fibroblasts and B cells showed attenuated canonical NF-κB response and propensity to cell death mediated by TNF superfamily members. Both SHARPIN- and HOIP-deficient patients showed substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient patient with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical role of LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.

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Project description:One of the ubiquitin ligases, LUBAC, is a trimetric complex composed of SHARPIN, HOIL-1, and HOIP. LUBAC works at the proximal TCR signaling pathway allowing normal Treg development. We used microarrays to detail the global programme of gene expression underlying LUBAC-mediated signaling pathway in Treg cells.

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Project description:Loss-of-expression and loss-of-function mutations in HOIL1 (RBCK1) results in disruption of the linear ubiquitination assembly complex (LUBAC). Impairment of LUBAC results in impaired NF-kB activation in response to TNF and IL-1b in fibroblastic cells, but also display enhanced pro-inflammatory responses to TNF and IL-1b in leukocytes. Autosomal recessive complete human HOIL-1/RBCK1 deficiency is a new disorder with unbalanced cellular responses to pro-inflammatory cytokines, resulting in the paradoxical association of auto-inflammation and pyogenic bacterial disease, as well as the surprising development of muscular amylopectinosis. The genome-wide gene expression analysis showed that human HOIL-1 deficiency results in impaired NF-B activation in response to TNF- and IL-1 in fibroblastic cells.

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Site-specific ubiquitination of the E3 ligase HOIP regulates apoptosis and immune signaling

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Genome-wide expression change by SHARPIN knockdown in MCF-7 cells

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Transcriptional analysis of whole blood in patients with auto-inflammatory disorders

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Transcriptional profiling of post-positive selection thymocytes from HOIL- and SHARPIN-deficient mice

Project description:Mice lacking components of the linear ubiquitin chain assembly complex (LUBAC) exhibit defects in thymocyte differentiation. To determine how two LUBAC components, HOIL and SHARPIN, mediate their effects, we purified thymocytes from CD4Cre Hoil-fl/fl or Sharpin-cpdm mice and compared their transcriptional profile to WT controls. We focused on the CD69+ MHCI low and CD69+ MHCI high subsets that follow positive selection.

2016-10-30 | GSE74552 | GEO

Effect of depletion of HOIP on gene expression during B16-F10 melanoma tumor development in immunedeficinet mice.

Project description:To investigate the cooperative function LUBAC E3 ligase complex during tumor development, we established HOIP-knockout B16-F10 murine melanoma cell lines.

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