Dominant negative OTULIN-related autoinflammatory syndrome

Davidson, S; Shibata, Y; Collard, S; Zheng, H; Kong, K; Sun, JM; Laohamonthonkul, P; Cerra, A; Kratina, T; CIRCA; AADRY; Li, MWY; Russell, C; van Beek, A; Kirk, EP; Walsh, R; Alqanatish, J; Almojali, A; Alsuwairi, W; Alrasheed, A; Lalaoui, N; Gray, PE; Komander, D; Masters, SL

Author(s): Davidson, S; Shibata, Y; Collard, S; Zheng, H; Kong, K; Sun, JM; Laohamonthonkul, P; Cerra, A; Kratina, T; CIRCA; AADRY; Li, MWY; Russell, C; van Beek, A; Kirk, EP; Walsh, R; Alqanatish, J; Almojali, A; Alsuwairi, W; Alrasheed, A; Lalaoui, N; Gray, PE; Komander, D; Masters, SL;
Details: Publication Year 2024-06-03,Volume 221,Issue #6,Page e20222171
Journal Title: Journal of Experimental Medicine
Publication Type: Research article
Abstract: OTU deubiquitinase with linear linkage specificity (OTULIN) regulates inflammation and cell death by deubiquitinating linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC). Biallelic loss-of-function mutations causes OTULIN-related autoinflammatory syndrome (ORAS), while OTULIN haploinsuffiency has not been associated with spontaneous inflammation. However, herein, we identify two patients with the heterozygous mutation p.Cys129Ser in OTULIN. Consistent with ORAS, we observed accumulation of linear ubiquitin chains, increased sensitivity to TNF-induced death, and dysregulation of inflammatory signaling in patient cells. While the C129S mutation did not affect OTULIN protein stability or binding capacity to LUBAC and linear ubiquitin chains, it did ablate OTULIN deubiquitinase activity. Loss of activity facilitated the accumulation of autoubiquitin chains on LUBAC. Altered ubiquitination of LUBAC inhibits its recruitment to the TNF receptor signaling complex, promoting TNF-induced cell death and disease pathology. By reporting the first dominant negative mutation driving ORAS, this study expands our clinical understanding of OTULIN-associated pathology.
Publisher: Rockefeller University Press
Keywords: Humans; Cell Death; Cell Membrane; Deubiquitinating Enzymes; *Inflammation/genetics; Syndrome; *Ubiquitin; Ubiquitin-Protein Ligase Complexes
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1084/jem.20222171
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-07-04 04:37:39

Last Modified: 2024-07-04 04:49:35