SPATA2 mediates the recruitment of CYLD to immune receptor complexes by bridging the interaction of CYLD with the linear ubiquitylation assembly complex (LUBAC) component HOIP. Whether SPATA2 exhibits functions independently of CYLD is unclear. Here, we show that, while Cyld and Spata2 mice are viable, double mutants exhibit highly penetrant perinatal lethality, indicating independent functions of SPATA2 and CYLD. CyldSpata2 fibroblasts show increased M1-linked TNFR1-SC ubiquitylation and, similar to CyldSpata2 macrophages and intestinal epithelial cells, elevated pro-inflammatory gene expression compared with Cyld or Spata2 cells. We show that SPATA2 competes with OTULIN for binding to HOIP via its PUB-interacting motif (PIM) and its zinc finger domain, thereby promoting autoubiquitylation of LUBAC. Consistently, increased pro-inflammatory signaling in CyldSpata2 cells depends on the presence of OTULIN. Our data therefore indicate that SPATA2 counteracts, independently of CYLD, the deubiquitylation of LUBAC by OTULIN and thereby attenuates LUBAC activity and pro-inflammatory signaling.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.celrep.2022.111961 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Identification of Genetic Variants in Progressive Supranuclear Palsy in Southeast Asia.
Mov Disord
October 2024
Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Background: Progressive supranuclear palsy (PSP) is largely a sporadic disease with few reported familial cases. Genome-wide association studies (GWAS) in sporadic PSP in Caucasian populations have identified MAPT as the most commonly associated genetic risk locus with the strongest effect size. At present there are limited data on genetic factors associated with PSP in Asian populations.
View Article and Find Full Text PDFProstaglandin E attenuates lung fibroblast differentiation via inactivation of yes-associated protein signaling.
FASEB J
October 2023
Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Ohio, Toledo, USA.
Prostaglandin E (PGE ) has been implicated in counteracting fibroblast differentiation by TGFβ1 during pulmonary fibrosis. However, the precise mechanism is not well understood. We show here that PGE via EP R and EP R inhibits the expression of mechanosensory molecules Lysyl Oxidase Like 2 (LOXL2), myocardin-related transcription factor A (MRTF-A), ECM proteins, plasminogen activation inhibitor 1 (PAI-1), fibronectin (FN), α-smooth muscle actin (α-SMA), and redox sensor (nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4)) required for TGFβ1-mediated fibroblast differentiation.
View Article and Find Full Text PDFNoncanonical HPV carcinogenesis drives radiosensitization of head and neck tumors.
Proc Natl Acad Sci U S A
August 2023
Department of Otolaryngology/Head and Neck Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
We analyzed transcriptional data from 104 HPV+ (Human papillomavirus) HNSCC (head and neck squamous cell carcinoma) tumors together with two publicly available sources to identify highly robust transcriptional programs (modules) which could be detected consistently despite heterogeneous sequencing and quantification methodologies. Among 22 modules identified, we found a single module that naturally subclassifies HPV+ HNSCC tumors based on a bimodal pattern of gene expression, clusters all atypical features of HPV+ HNSCC biology into a single subclass, and predicts patient outcome in four independent cohorts. The subclass-defining gene set was strongly correlated with Nuclear factor kappa B (NF-κB) target expression.
View Article and Find Full Text PDFA 3-gene signature comprising CDH4, STAT4 and EBV-encoded LMP1 for early diagnosis and predicting disease progression of nasopharyngeal carcinoma.
Discov Oncol
July 2023
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, 35053, Miaoli County, Taiwan.
Purpose: Nasopharyngeal carcinoma is highly metastatic but difficult to detect in its early stages. It is critical to develop a simple and highly efficient molecular diagnostic method for early detection of NPC in clinical biopsies.
Methods: The transcriptomic data of primary NPC cell strains were used as a discovery tool.
A necroptosis gene signature predicts prostate cancer recurrence, and is linked to somatic mutation, therapeutic landscape, and immune infiltration.
Am J Transl Res
April 2023
Department of Rehabilitation Medicine, The Second Affiliated Hospital of Nanchang University Nanchang 330006, Jiangxi, China.
Objective: Necroptosis, a type of programmed necrotic cell death, has been implicated in cancer biology and therapeutics. Improved risk stratification is required for prostate carcinoma in individuals. In view of the importance of necroptosis, this work proposed a necroptosis-based genetic model for recurrence prediction, and clarified its characteristics.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!