Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE199445 | GEO | 2023/04/01
REPOSITORIES: GEO
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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 by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. 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 tumor necrosis factor receptor-mediated nuclear factor 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 against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.
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Project description:IRF4 Haploinsufficiency Impairs Affinity Maturation
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Project description:The germinal center (GC) reaction is a coordinated and dynamic ensemble of cells and processes that mediate the maturation and selection of high-affinity GC B cells (GCBs) from lower-affinity precursors and ultimately results in plasma cell and memory cell fates that exit the GC. It is of great interest to identify intrinsic and extrinsic factors that control the selection process. The transcription factor IRF4, induced upon BCR and CD40 signaling, is essential for the acquisition of plasma cell and GCB cell fates. We hypothesized that beyond this early requirement, IRF4 continuously operates at later phases of the B cell response. We show that IRF4 is expressed in GCBs at levels greater than seen in resting cells and plays a role in efficient selection of high-affinity GCBs. Halving Irf4 gene copy number in an Ag-specific murine B cell model, we found that Ag presentation, isotype switching, GC formation and zonation, somatic hypermutation rates, and proliferation were comparable with cells with a full Irf4 allelic complement. In contrast, Irf4 haploinsufficient GCBs exhibited impaired generation of high-affinity cells. Mechanistically, we demonstrate suboptimal Blimp-1 regulation among high-affinity Irf4 haploinsufficient GCBs. Furthermore, in cotransfer settings, we observed a marked disadvantage of Irf4 haploinsufficient cells for GC entry, evidential of ineffective recruitment of T cell help. We propose that, analogous to its role in early GC entry, IRF4 continues to function in the late phase of the Ab response to promote productive T follicular helper cell interactions and to activate optimal Blimp-1 expression during GC selection and affinity maturation.
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Project description:ADP-ribosylation is an important post-translational protein modification that regulates diverse biological processes, controlled by dedicated transferases and hydrolases. Here we show that frequent deletions (~30%) of the MACROD2 mono-ADP-ribosylhydrolase locus in human colorectal cancer (CRC) cause impaired PARP1 transferase activity in a gene dosage-dependent manner. MACROD2 haploinsufficiency alters DNA repair and sensitivity to DNA damage, and results in chromosome instability. Heterozygous and homozygous depletion of Macrod2 enhances intestinal tumorigenesis in ApcMin/+ mice and the growth of human CRC xenografts. MACROD2 deletion in sporadic CRC is associated with the extent of chromosome instability, independent of clinical parameters and other known genetic drivers. We conclude that MACROD2 acts as a haploinsufficient tumor suppressor, with loss of function promoting chromosome instability thereby driving cancer evolution.
2018-06-05 | GSE115145 | GEO
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
Project description:Rationale- NAA15 is a component of the N-terminal (Nt) acetyltransferase complex, NatA. The mechanism by which NAA15 haploinsufficiency causes congenital heart disease (CHD) remains unknown. To better understand molecular processes by which NAA15 haploinsufficiency perturbs cardiac development, we introduced NAA15 variants into human induced pluripotent stem cells (iPSCs) and assessed the consequences of these mutations on RNA and protein expression. Objective- We aim to understand the role of NAA15 haploinsufficiency in cardiac development by investigating proteomic effects on NatA complex activity, and identifying proteins dependent upon a full amount of NAA15.Methods and Results - We introduced heterozygous LoF, compound heterozygous and missense residues (R276W) in iPS cells using CRISPR/Cas9. Haploinsufficient NAA15 iPS cells differentiate into cardiomyocytes, unlike NAA15-null iPS cells, presumably due to altered composition of NatA. Mass spectrometry (MS) analyses reveal ~80% of identified iPS cell NatA targeted proteins displayed partial or complete Nt-acetylation. Between null and haploinsufficient NAA15 cells Nt-acetylation levels of 32 and 9 NatA-specific targeted proteins were reduced, respectively. Similar acetylation loss in few proteins occurred in NAA15 R276W iPSCs. In addition, steady-state protein levels of 562 proteins were altered in both null and haploinsufficient NAA15 cells; eighteen were ribosomal-associated proteins. At least four proteins were encoded by genes known to cause autosomal dominant CHD. Conclusions - These studies define a set of human proteins that requires a full NAA15 complement for normal synthesis and development. A 50% reduction in the amount of NAA15 alters levels of at least 562 proteins and Nt-acetylation of only 9 proteins. One or more modulated proteins are likely responsible for NAA15-haploinsufficiency mediated CHD. Additionally, genetically engineered iPS cells provide a platform for evaluating the consequences of amino acid sequence variants of unknown significance on NAA15 function.
2020-11-05 | GSE160809 | GEO
Project description:NAA15 is a component of the NatA complex that acetylates amino terminal (Nt) protein residues and influences protein synthesis. We identified multiple damaging NAA15 variants in congenital heart disease patients, including four loss-of-function (LoF) variants, one missense (R276W) de novo variant and 15 rare inherited missense variants. To understand the effects of these variants on NatA complex activity, we introduced heterozygous LoF, compound heterozygous and missense residues iPS cells using CRISPR/Cas9. Haploinsufficient NAA15 iPS cells differentiate into cardiomyocytes, unlike NAA15-null iPS cells, presumably due to alterations in the amount and composition of the NatA complex. Mass spectrometry (MS)-based N-terminomics analyses showed that nearly 80% of iPS cell proteins displayed partial or complete Nt-acetylation. Between null and haploinsufficient NAA15 cells, 32 and 9 NatA-specific targeted proteins differed in their Nt-acetylation degree, respectively. In addition, the steady-state protein levels of more than 560 proteins were altered in mutant compared to wild type cells. While most NatA-specific Nt-acetylated proteins were fully acetylated, ~19 proteins were partially acetylated. NAA15-haploinsufficiency abrogated Nt-acetylation of 4 of these proteins but did not affect the acetylation of the other 15 proteins. Similar patterns of acetylation loss in few proteins were observed in both NAA15 haploinsufficient and NAA15 R276W iPS cells. These studies define human proteins that appear to require the full NAA15 complex for normal acetylation and imply that deficiencies in one or more of these NAA15 target proteins contribute to normal cardiac development. The current dataset contains all N-terminomics data related to this study.
2021-08-30 | PXD018013 | Pride
Project description:NAA15 is a component of the NatA complex that acetylates amino terminal (Nt) protein residues and influences protein synthesis. We identified multiple damaging NAA15 variants in congenital heart disease patients, including four loss-of-function (LoF) variants, one missense (R276W) de novo variant and 15 rare inherited missense variants. To understand the effects of these variants on NatA complex activity, we introduced heterozygous LoF, compound heterozygous and missense residues iPS cells using CRISPR/Cas9. Haploinsufficient NAA15 iPS cells differentiate into cardiomyocytes, unlike NAA15-null iPS cells, presumably due to alterations in the amount and composition of the NatA complex. Mass spectrometry (MS)-based N-terminomics analyses showed that nearly 80% of iPS cell proteins displayed partial or complete Nt-acetylation. Between null and haploinsufficient NAA15 cells, 32 and 9 NatA-specific targeted proteins differed in their Nt-acetylation degree, respectively. In addition, the steady-state protein levels of more than 560 proteins were altered in mutant compared to wild type cells. While most NatA-specific Nt-acetylated proteins were fully acetylated, ~19 proteins were partially acetylated. NAA15-haploinsufficiency abrogated Nt-acetylation of 4 of these proteins but did not affect the acetylation of the other 15 proteins. Similar patterns of acetylation loss in few proteins were observed in both NAA15 haploinsufficient and NAA15 R276W iPS cells. These studies define human proteins that appear to require the full NAA15 complex for normal acetylation and imply that deficiencies in one or more of these NAA15 target proteins contribute to normal cardiac development. The current dataset contains all shotgun proteomics data related to this study.
2021-07-07 | PXD017672 | Pride