Dominant negative OTULIN-related autoinflammatory syndrome.

Autor:	Davidson S; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Australia., Shibata Y; Department of Medical Biology, The University of Melbourne, Parkville, Australia.; Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia., Collard S; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Australia., Zheng H; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Australia., Kong K; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Australia., Sun JM; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Australia., Laohamonthonkul P; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Australia., Cerra A; Department of Medical Biology, The University of Melbourne, Parkville, Australia.; Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia., Kratina T; Peter MacCallum Cancer Centre , Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia., Li MWY; School of Clinical Medicine, University of New South Wales , Randwick, Australia.; Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Randwick, Australia., Russell C; Department of Paediatric Surgery, Sydney Children's Hospital, Randwick, Australia., van Beek A; Department of General Paediatrics, Sydney Children's Hospital, Randwick, Australia., Kirk EP; School of Clinical Medicine, University of New South Wales , Randwick, Australia.; Centre for Clinical Genetics, Sydney Children's Hospital , Randwick, Australia.; New South Wales Health Pathology Randwick Genomics Laboratory , Randwick, Australia., Walsh R; New South Wales Health Pathology Randwick Genomics Laboratory , Randwick, Australia., Alqanatish J; Pediatric Rheumatology, King Abdullah Specialist Children's Hospital, National Guard Health Affairs , Riyadh, Saudi Arabia.; King Abdullah International Medical Research Center , Riyadh, Saudi Arabia.; College of Medicine, King Saud Bin Abdulaziz University for Health Sciences , Riyadh, Saudi Arabia., Almojali A; Pediatric Rheumatology, King Abdullah Specialist Children's Hospital, National Guard Health Affairs , Riyadh, Saudi Arabia.; King Abdullah International Medical Research Center , Riyadh, Saudi Arabia.; College of Medicine, King Saud Bin Abdulaziz University for Health Sciences , Riyadh, Saudi Arabia., Alsuwairi W; Pediatric Rheumatology, King Abdullah Specialist Children's Hospital, National Guard Health Affairs , Riyadh, Saudi Arabia.; King Abdullah International Medical Research Center , Riyadh, Saudi Arabia.; College of Medicine, King Saud Bin Abdulaziz University for Health Sciences , Riyadh, Saudi Arabia., Alrasheed A; Pediatric Rheumatology, King Abdullah Specialist Children's Hospital, National Guard Health Affairs , Riyadh, Saudi Arabia.; King Abdullah International Medical Research Center , Riyadh, Saudi Arabia.; College of Medicine, King Saud Bin Abdulaziz University for Health Sciences , Riyadh, Saudi Arabia., Lalaoui N; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.; Peter MacCallum Cancer Centre , Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia., Gray PE; Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Randwick, Australia.; University of Western Sydney , Sydney, Australia., Komander D; Department of Medical Biology, The University of Melbourne, Parkville, Australia.; Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia., Masters SL; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Australia.; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research , Clayton, Australia.; Department of Molecular and Translational Science, Monash University, Clayton, Australia.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2024 Jun 03; Vol. 221 (6). Date of Electronic Publication: 2024 Apr 17.
DOI:	10.1084/jem.20222171
Abstrakt:	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. (© 2024 Davidson et al.)
Databáze:	MEDLINE
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