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Pyoderma gangrenosum caused by molecular uncoupling of OTULIN catalytic activity and LUBAC binding

ABSTRACT: Pyoderma gangrenosum caused by molecular uncoupling of OTULIN catalytic activity and LUBAC binding

PROVIDER: PRJNA1281734 | ENA |

REPOSITORIES: ENA

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Pyoderma gangrenosum caused by molecular uncoupling of OTULIN catalytic activity and LUBAC binding

Project description:Pyoderma gangrenosum caused by molecular uncoupling of OTULIN catalytic activity and LUBAC binding

| PRJNA1281733 | ENA

Regulation of the endosomal SNX27 retromer by OTULIN

Project description:OTULIN specifically hydrolyzes methionine1 (Met1)-linked ubiquitin chains conjugated by LUBAC (linear ubiquitin chain assembly complex). Using mass spectrometry, we discovered an interaction of OTULIN with SNX27 (sorting nexin 27), an adaptor of the endosomal retromer complex responsible for protein recycling to the cell surface. The C-terminal PDZ binding motif (PDZbm) in OTULIN associates with the cargo-binding site in the PDZ domain of SNX27. By solving the structure of the OTU domain in complex with the PDZ domain, we demonstrate that a second interface contributes to the selective, high affinity interaction of OTULIN and SNX27. SNX27 does not affect OTULIN catalytic activity, OTULIN-LUBAC binding or Met1-linked ubiquitin chain homeostasis. However, via association OTULIN antagonizes SNX27-dependent cargo loading, binding of SNX27 to the retromer subunit VPS26 and endosome-to-membrane trafficking. Thus, we define an additional, non-catalytic function of OTULIN in the regulation of retromer assembly and protein recycling to the cell surface.

2019-09-25 | PXD012082 | Pride

Analysis of LPS-induced gene expression of OTULIN-deficient murine macrophages by RNA sequencing

Project description:In order to unravel the role of the linear deubiquitinase OTULIN in LPS-induced gene expression in macrophages, we performed RNA-sequencing on primary bone marrow-derived macrophages of mice lacking OTULIN selectively in myeloid cells. Myeloid cell-specific OTULIN knock-out mice develop an auto-inflammatory phenotype and macrophages derived from these mice display increased LPS-induced inflammasome activation and cell death. Through analysing LPS-induced gene expression analyses on OTULIN-deficient macrophages we aimed to identify signalling pathways and genes that regulate inflammasome activation and cell death in these cells, in order to get new insights on the molecular events that regulate the development of autoinflammation in myeloid cell specific OTULIN-deficient mice.

2023-05-24 | GSE233229 | GEO

Analysis of skin of keratinocyte-specific OTULIN-deficient mice by single-cell RNA-sequencing

Project description:In order to unravel the functional role of the linear deubiquitinase OTULIN, we performed single-cell RNA-sequencing on total skin of mice lacking OTULIN selectively in keratinocytes. Keratinocyte-specific OTULIN knock-out (KO) mice develop delineated inflammatory lesion. Through single-cell analysis on lesional and non-lesional skin of mice lacking OTULIN in keratinocytes, we could identify signalling pathways through which these inflammatory lesions appear, allowing us to get new insights on the molecular events that regulate skin homeostasis and mediate skin inflammation.

2021-08-03 | GSE162394 | GEO

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin

Project description:We performed single-cell RNA sequencing (scRNASeq) on cryopreserved peripheral blood mononuclear cells (PBMCs) of healthy controls and OTULIN haploinsufficient patients in order to clarify the perturbation, if any, of cellular phenotypes in various leukocyte subsets in vivo at basal state attributable to OTULIN haploinsufficiency.

2023-04-01 | GSE199445 | GEO

Otulin inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice

Project description:Mice with epidermal keratinocyte specific knockout of OTULIN develop inflammatory skin disease. To study the inflammatory response we used Lexogen 3´mRNA sequencing to compare the gene expression profiles in the skin of OTULIN epidermis specific knockout and control mice.

2021-08-23 | GSE180024 | GEO

A linear diubiquitin-based probe for efficient and selective detection of the deubiquitinating enzyme OTULIN

Project description:The methionine1 (M1)-specific deubiquitinase OTULIN acts as a negative regulator of NF-ΚB signaling and immune homeostasis. By replacing G76 in distal ubiquitin by dehydroalanine we designed the diubiquitin (diUb) probe UbG76Dha-Ub (OTULIN ABP) that couples to the catalytic site of OTULIN and thereby captures OTULIN in its active conformation. OTULIN ABP displays high selectivity for OTULIN and is not labeling to other M1-specific DUB including CYLD. In fact, labeling of USP5/IsopeptidaseT was the only detectable cross-reactivity. Further, ATP-dependent association of UbG76Dha-Ub probe with E1 activating enzymes induces assembly of polyOTULIN ABP chains, but USP5 labelling and E1 binding was abolished by deleting the C-terminal glycine in proximal ubiquitin (UbG76Dha-UbΔG76: OTULIN ABPΔG76). Pull-downs demonstrate that substrate-bound OTULIN associates with the linear ubiquitin chain assembly complex (LUBAC). Thus, we present a highly selective DUB for OTULIN that will facilitate studying the cellular function of this critical deubiquitinase.

2017-09-19 | PXD006868 | Pride

Large-scale proteome and ubiquitination landscape of patients with OTULIN haploinsufficiency Part1 of 3

Project description:The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded on chromosome 5p. The patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infections. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but TNF-receptor NF-κB-signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts — but not leukocytes — facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies to α-toxin contribute to incomplete clinical penetrance. By disrupting cell-intrinsic immunity to α-toxin in non-leukocytic cells, human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease.

2022-06-13 | PXD032727 | Pride

Identification of OTULIN substrates

Project description:Lysates from WT- and C129A-Otulin expressing cells were each subjected to serial enrichment using FLAG-anti-linear polyubiquitin TUBEs (tandem ubiquitin binding elements) followed by FLAG-anti-K48-linked polyubiquitin TUBEs.

2018-01-22 | MSV000081959 | MassIVE

IL-12/IL-23 blockade reveals patterns of asynchronous inflammation in pyoderma gangrenosum

Project description:Pyoderma Gangrenosum (PG) is a rare and extremely painful neutrophilic dermatosis associated with non-healing cutaneous ulcers affecting 3-10 individuals per million people. The etiology and molecular pathogenetic events of this disease are yet unknown. To investigate how this therapeutic regime shaped the underlying inflammatory response, we performed spatial transcriptomics on lesional biopsies from patients before and after ustekinumab treatment. Our study provides high resolution temporal insights into the inflammatory environment of PG lesional skin following treatment with IL-12/IL-23 blockade in two patients with classic and peristomal PG. This work highlights that while inhibition of representative cytokines of the Th1 and Th17 pathways shows promise as a treatment for PG patients, it does not dampen all active inflammatory pathways.

2024-08-28 | GSE274489 | GEO

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