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

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-?B 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-defi

SUBMITTER: Dr. David Komander 

PROVIDER: S-SCDT-EMM-2018-09324 | biostudies-other |

REPOSITORIES: biostudies-other