OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death.,EMBO Molecular Medicine

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OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death.
EMBO Molecular Medicine ( IF 9.0 ) Pub Date : 2019-03-01 , DOI: 10.15252/emmm.201809324
Rune Busk Damgaard ₁ , Paul R Elliott ₂ , Kirby N Swatek ₂ , Eamonn R Maher ₃ , Polina Stepensky _{4,

5} , Orly Elpeleg _{4,

6} , David Komander _{1,

7,

8} , Yackov Berkun _{9,

10}

Affiliation

Medical Research Council Laboratory of Molecular Biology, Cambridge, UK
Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
Department of Medical Genetics, University of Cambridge and Cambridge NIHR Biomedical Research Centre, Cambridge, UK.
Hebrew University Hadassah Medical School, Jerusalem, Israel.
Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Monique and Jacques Roboh Department of Genetic Research, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research, Parkville Melbourne, VIC, Australia.
Department of Medical Biology, The University of Melbourne, Melbourne VIC, Australia.
Hebrew University Hadassah Medical School, Jerusalem, Israel
Department of Pediatrics, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

The deubiquitinase OTULIN removes methionine-1 (M1)-linked polyubiquitin signals conjugated by the linear ubiquitin chain assembly complex (LUBAC) and is critical for preventing TNF-driven inflammation in OTULIN-related autoinflammatory syndrome (ORAS). Five ORAS patients have been reported, but how dysregulated M1-linked polyubiquitin signalling causes their symptoms is unclear. Here, we report a new case of ORAS in which an OTULIN-Gly281Arg mutation leads to reduced activity and stability in vitro and in cells. In contrast to OTULIN-deficient monocytes, in which TNF signalling and NF-κB activation are increased, loss of OTULIN in patient-derived fibroblasts leads to a reduction in LUBAC levels and an impaired response to TNF Interestingly, both patient-derived fibroblasts and OTULIN-deficient monocytes are sensitised to certain types of TNF-induced death, and apoptotic cells are evident in ORAS patient skin lesions. Remarkably, haematopoietic stem cell transplantation leads to complete resolution of inflammatory symptoms, including fevers, panniculitis and diarrhoea. Therefore, haematopoietic cells are necessary for clinical manifestation of ORAS Together, our data suggest that ORAS pathogenesis involves hyper-inflammatory immune cells and TNF-induced death of both leukocytes and non-haematopoietic cells.

中文翻译：

ORAS 中的 OTULIN 缺陷导致细胞类型特异性 LUBAC 降解、TNF 信号传导失调和细胞死亡。

去泛素化酶 OTULIN 可去除由线性泛素链组装复合物 (LUBAC) 偶联的甲硫氨酸-1 (M1) 连接的多聚泛素信号，并且对于预防 OTULIN 相关自身炎症综合征 (ORAS) 中 TNF 驱动的炎症至关重要。已报告了 5 名 ORAS 患者，但 M1 连接的多聚泛素信号传导失调如何导致他们的症状尚不清楚。在这里，我们报告了一个新的 ORAS 病例，其中 OTULIN-Gly281Arg 突变导致体外和细胞中的活性和稳定性降低。与 OTULIN 缺陷型单核细胞相比，其中 TNF 信号传导和 NF-κB 活化增加，患者来源的成纤维细胞中 OTULIN 的缺失导致 LUBAC 水平降低和对 TNF 的反应受损。患者来源的成纤维细胞和 OTULIN 缺陷的单核细胞都对某些类型的 TNF 诱导的死亡敏感，并且在 ORAS 患者皮肤病变中凋亡细胞很明显。值得注意的是，造血干细胞移植可以完全缓解炎症症状，包括发烧、脂膜炎和腹泻。因此，造血细胞是 ORAS 临床表现所必需的。我们的数据表明，ORAS 的发病机制涉及高炎症免疫细胞和 TNF 诱导的白细胞和非造血细胞死亡。

更新日期：2019-03-07

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