{"doi":"10.1101/2020.01.27.919076","title":"Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death","abstract":"Abstract SHARPIN, together with RNF31/HOIP and RBCK1/HOIL1, form the linear ubiquitin chain assembly complex (LUBAC) E3 ligase that catalyzes M1-linked poly-ubiquitination. Mutations in RNF31/HOIP and RBCK/HOIL1 in humans and Sharpin in mice lead to auto-inflammation and immunodeficiency but the mechanism underlying the immune dysregulation remains unclear. We now show that the phenotype of the Sharpin -/- mice is dependent on CYLD, the deubiquitinase that removes K63-linked poly-ubiquitin chains. The dermatitis, disrupted splenic architecture, and loss of Peyer’s patches in the Sharpin -/- mice were fully reversed in Sharpin -/- Cyld -/- mice. There is enhanced association of RIPK1 with the death-inducing signaling complex (DISC) following TNF stimulation in Sharpin -/- cells, and this is dependent on CYLD since it is reversed in Sharpin -/- Cyld -/- cells. Enhanced RIPK1 recruitment to the DISC in Sharpin -/- cells correlated with impaired phosphorylation of CYLD at serine 418, a modification reported to inhibit its enzymatic activity. The dermatitis in the Sharpin -/- mice was also ameliorated by the conditional deletion of Cyld using LysM-cre or Cx3cr1-cre indicating that CYLD-dependent death of myeloid cells is inflammatory. Our studies reveal that under physiological conditions, TNF- and RIPK1-dependent cell death is suppressed by the linear ubiquitin-dependent inhibition of CYLD. The Sharpin -/- phenotype illustrates the pathological consequences when CYLD inhibition fails. Short Summary In the absence of SHARPIN, cells fail to properly regulate the deubiquitinase CYLD, leading to RIPK1-mediated cell death. Deletion of Cyld reverses the sensitivity of Sharpin -/- cells to TNF-induced cell death, as well as the multi-organ inflammation and immune dysfunction observed in Sharpin -/- mice.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":124564,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9606,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":293131,"name":"John P. Sundberg","orcid":"0000-0002-1523-5430","position":1,"is_corresponding":false},{"id":6252,"name":"Shao‐Cong Sun","orcid":"0000-0001-7353-9400","position":2,"is_corresponding":false},{"id":569671,"name":"Virginia Gillespie","orcid":"0000-0003-3387-0021","position":3,"is_corresponding":false},{"id":105288,"name":"Peter S. Heeger","orcid":"0000-0003-4673-6913","position":4,"is_corresponding":false},{"id":490523,"name":"Huabao Xiong","orcid":"0000-0003-0180-2104","position":5,"is_corresponding":false},{"id":231494,"name":"Sérgio A. Lira","orcid":"0000-0002-6742-3089","position":6,"is_corresponding":false},{"id":490524,"name":"Adrian T. Ting","orcid":"0000-0003-0653-9923","position":7,"is_corresponding":false},{"id":490520,"name":"Rosalind L. Ang","orcid":"0000-0001-5836-4243","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:15:11.632153Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}