6I9C

Structure of the OTU domain of OTULIN G281R mutant

Summary for 6I9C

• Entry DOI: 10.2210/pdb6i9c/pdb
• Descriptor: Ubiquitin thioesterase otulin, GLYCEROL, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: met1-specific deubiquitinase, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 31668.79

Authors

Damgaard, R.B.,Elliott, P.R.,Swatek, K.N.,Maher, E.R.,Stepensky, P.,Elpeleg, O.,Komander, D.,Berkun, Y. (deposition date: 2018-11-22, release date: 2019-03-06, Last modification date: 2024-05-15)

Primary citation

Damgaard, R.B.,Elliott, P.R.,Swatek, K.N.,Maher, E.R.,Stepensky, P.,Elpeleg, O.,Komander, D.,Berkun, Y.
OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death.
Embo Mol Med, 11:-, 2019

PubMed 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 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.

PubMed: 30804083
DOI: 10.15252/emmm.201809324

Experimental method

X-RAY DIFFRACTION (1.77 Å)