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

Damgaard, RB; Elliott, PR; Swatek, KN; Maher, ER; Stepensky, P; Elpeleg, O; Komander, D; Berkun, Y

Author(s): Damgaard, RB; Elliott, PR; Swatek, KN; Maher, ER; Stepensky, P; Elpeleg, O; Komander, D; Berkun, Y;
Details: Publication Year 2019-02-25,Volume 11,Issue #3,Page pii: e9324
Journal Title: EMBO Molecular Medicine
Publication Type: Journal Article
Abstract: 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-kappaB 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.
Publisher: EMBO Press
Research Division(s): Ubiquitin Signalling
PubMed ID: 30804083
Publisher's Version: https://doi.org/10.15252/emmm.201809324
Open Access at Publisher's Site: https://doi.org/10.15252/emmm.201809324
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2019-03-13 11:54:05

Last Modified: 2019-04-01 08:35:44