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Article ; Online: Valosin-containing protein-regulated endoplasmic reticulum stress causes NOD2-dependent inflammatory responses

Maryam Ghalandary / Yue Li / Thomas Fröhlich / Thomas Magg / Yanshan Liu / Meino Rohlfs / Sebastian Hollizeck / Raffaele Conca / Tobias Schwerd / Holm H. Uhlig / Philip Bufler / Sibylle Koletzko / Aleixo M. Muise / Scott B. Snapper / Fabian Hauck / Christoph Klein / Daniel Kotlarz

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 12

Abstract: Abstract NOD2 polymorphisms may affect sensing of the bacterial muramyl dipeptide (MDP) and trigger perturbed inflammatory responses. Genetic screening of a patient with immunodeficiency and enteropathy revealed a rare homozygous missense mutation in the ...

Abstract	Abstract NOD2 polymorphisms may affect sensing of the bacterial muramyl dipeptide (MDP) and trigger perturbed inflammatory responses. Genetic screening of a patient with immunodeficiency and enteropathy revealed a rare homozygous missense mutation in the first CARD domain of NOD2 (ENST00000300589; c.160G > A, p.E54K). Biochemical assays confirmed impaired NOD2-dependent signaling and proinflammatory cytokine production in patient’s cells and heterologous cellular models with overexpression of the NOD2 mutant. Immunoprecipitation-coupled mass spectrometry unveiled the ATPase valosin-containing protein (VCP) as novel interaction partner of wildtype NOD2, while the binding to the NOD2 variant p.E54K was abrogated. Knockdown of VCP in coloncarcinoma cells led to impaired NF-κB activity and IL8 expression upon MDP stimulation. In contrast, tunicamycin-induced ER stress resulted in increased IL8, CXCL1, and CXCL2 production in cells with knockdown of VCP, while enhanced expression of these proinflammatory molecules was abolished upon knockout of NOD2. Taken together, these data suggest that VCP-mediated inflammatory responses upon ER stress are NOD2-dependent.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: ARPC1B binds WASP to control actin polymerization and curtail tonic signaling in B cells

Gabriella Leung / Yuhuan Zhou / Philip Ostrowski / Sivakami Mylvaganam / Parastoo Boroumand / Daniel J. Mulder / Conghui Guo / Aleixo M. Muise / Spencer A. Freeman

JCI Insight, Vol 6, Iss

2021 Volume 23

Abstract: Immune cells exhibit low-level, constitutive signaling at rest (tonic signaling). Such tonic signals are required for fundamental processes, including the survival of B lymphocytes, but when they are elevated by genetic or environmental causes, they can ... ...

Abstract	Immune cells exhibit low-level, constitutive signaling at rest (tonic signaling). Such tonic signals are required for fundamental processes, including the survival of B lymphocytes, but when they are elevated by genetic or environmental causes, they can lead to autoimmunity. Events that control ongoing signal transduction are, therefore, tightly regulated by submembrane cytoskeletal polymers like F-actin. The actin-binding proteins that underpin the process, however, are poorly described. By investigating patients with ARPC1B deficiency, we report that ARPC1B-containing ARP2/3 complexes are stimulated by Wiskott Aldrich Syndrome protein (WASP) to nucleate the branched actin networks that control tonic signaling from the B cell receptor (BCR). Despite an upregulation of ARPC1A, ARPC1B-deficient cells were not capable of WASP-mediated nucleation by ARP2/3, and this caused the loss of WASP-dependent structures, including podosomes in macrophages and lamellipodia in B cells. In the B cell compartment, ARPC1B deficiency also led to weakening of the cortical F-actin cytoskeleton that normally curtails the diffusion of BCRs and ultimately resulted in increased tonic lipid signaling, oscillatory calcium release from the endoplasmic reticulum (ER), and phosphorylated Akt. These events contributed to skewing the threshold for B cell activation in response to microbial-associated molecular patterns (MAMPs). Thus, ARPC1B is critical for ARP2/3 complexes to control steady-state signaling of immune cells.
Keywords	Cell biology ; Immunology ; Medicine ; R
Subject code	570
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease

Neel Dhingani / Conghui Guo / Jie Pan / Qi Li / Neil Warner / Sasha Jardine / Gabriella Leung / Daniel Kotlarz / Claudia Gonzaga-Jauregui / Christoph Klein / Scott B. Snapper / Víctor Manuel Navas-López / Aleixo M. Muise

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 11

Abstract: Abstract Very early onset inflammatory bowel disease (VEOIBD) denotes children with onset of IBD before six years of age. A number of monogenic disorders are associated with VEOIBD including tetratricopeptide repeat domain 7A (TTC7A) deficiency. TTC7A- ... ...

Abstract	Abstract Very early onset inflammatory bowel disease (VEOIBD) denotes children with onset of IBD before six years of age. A number of monogenic disorders are associated with VEOIBD including tetratricopeptide repeat domain 7A (TTC7A) deficiency. TTC7A-deficiency is characterized by apoptotic colitis in milder cases with severe intestinal atresia and immunodeficiency in cases with complete loss of protein. We used whole exome sequencing in a VEOIBD patient presenting with colitis characterized by colonic apoptosis and no identified known VEOIBD variants, to identify compound heterozygous deleterious variants in the Ubiquitin protein ligase E3 component N-recognin 5 (UBR5) gene. Functional studies demonstrated that UBR5 co-immunoprecipitates with the TTC7A and the UBR5 variants had reduced interaction between UBR5 and TTC7A. Together this implicates UBR5 in regulating TTC7A signaling in VEOIBD patients with apoptotic colitis.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease

Julie E. Horowitz / Neil Warner / Jeffrey Staples / Eileen Crowley / Nehal Gosalia / Ryan Murchie / Cristopher Van Hout / Karoline Fiedler / Gabriel Welch / Alejandra Klauer King / Jeffrey G. Reid / John D. Overton / Aris Baras / Alan R. Shuldiner / Anne Griffiths / Omri Gottesman / Aleixo M. Muise / Claudia Gonzaga-Jauregui

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 10

Abstract: Abstract Inflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD ... ...

Abstract	Abstract Inflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0–18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn’s Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7–10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn’s Disease.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Novel CARMIL2 loss-of-function variants are associated with pediatric inflammatory bowel disease

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 13

Abstract: Abstract CARMIL2 is required for CD28-mediated co-stimulation of NF-κB signaling in T cells and its deficiency has been associated with primary immunodeficiency and, recently, very early onset inflammatory bowel disease (IBD). Here we describe the ... ...

Abstract	Abstract CARMIL2 is required for CD28-mediated co-stimulation of NF-κB signaling in T cells and its deficiency has been associated with primary immunodeficiency and, recently, very early onset inflammatory bowel disease (IBD). Here we describe the identification of novel biallelic CARMIL2 variants in three patients presenting with pediatric-onset IBD and in one with autoimmune polyendocrine syndrome (APS). None manifested overt clinical signs of immunodeficiency before their diagnosis. The first patient presented with very early onset IBD. His brother was found homozygous for the same CARMIL2 null variant and diagnosed with APS. Two other IBD patients were found homozygous for a nonsense and a missense CARMIL2 variant, respectively, and they both experienced a complicated postoperative course marked by severe infections. Immunostaining of bowel biopsies showed reduced CARMIL2 expression in all the three patients with IBD. Western blot and immunofluorescence of transfected cells revealed an altered expression pattern of the missense variant. Our work expands the genotypic and phenotypic spectrum of CARMIL2 deficiency, which can present with either IBD or APS, aside from classic immunodeficiency manifestations. CARMIL2 should be included in the diagnostic work-up of patients with suspected monogenic IBD.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Association Between a Multi-Locus Genetic Risk Score and Inflammatory Bowel Disease

Pingzhao Hu / Aleixo M. Muise / Xiang Xing / John H. Brumell / Mark S. Silverberg / Wei Xu

Bioinformatics and Biology Insights, Vol 2013, Iss 7, Pp 143-

2013 Volume 152

Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2013-05-01T00:00:00Z
Publisher	SAGE Publishing
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Association between a Multi-Locus Genetic Risk Score and Inflammatory Bowel Disease

Pingzhao Hu / Aleixo M. Muise / Xiang Xing / John H. Brumell / Mark S. Silverberg / Wei Xu

Bioinformatics and Biology Insights, Vol

2013 Volume 7

Abstract: To date, the utility of single genetic markers to improve disease risk assessment still explains only a small proportion of genetic variance for many complex diseases. This missing heritability may be explained by additional variants with weak effects. ... ...

Abstract	To date, the utility of single genetic markers to improve disease risk assessment still explains only a small proportion of genetic variance for many complex diseases. This missing heritability may be explained by additional variants with weak effects. To discover and incorporate these additional genetic factors, statistical and computational methods must be evaluated and developed. We develop a multi-locus genetic risk score (GRS) based approach to analyze genes in NADPH oxidase complex which may result in susceptibility to development of inflammatory bowel disease (IBD). We find the complex is highly associated with IBD ( P = 7.86 × 10 –14 ) using the GRS-based association method. Similar results are also shown in permutation analysis ( P = 6.65 × 10 –11 ). Likelihood ratio test shows that the single nucleotide polymorphisms (SNPs) in the complex without nominal signals have significant contribution to the overall genetic effect within the complex ( P = 0.015). Our results show that the multi-locus GRS association model can improve the genetic risk assessment on IBD by taking into account both confirmed and as yet unconfirmed disease susceptibility variants.
Keywords	Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	SAGE Publishing
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

EMBO Molecular Medicine, Vol 10, Iss 4, Pp n/a-n/a (2018)

2018

Abstract: Abstract Herein, we report the first identification of biallelic‐inherited mutations in ALPI as a Mendelian cause of inflammatory bowel disease in two unrelated patients. ALPI encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that ...

Abstract	Abstract Herein, we report the first identification of biallelic‐inherited mutations in ALPI as a Mendelian cause of inflammatory bowel disease in two unrelated patients. ALPI encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll‐like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter‐subunit interactions, and heterologous expression in HEK293T cells demonstrated that all ALPI mutations were loss of function. ALPI mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide‐dependent signalling. Furthermore, ALPI expression was reduced in patients’ biopsies, and ALPI activity was undetectable in ALPI‐deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host–microbiota interactions and restraining host inflammatory responses. These results indicate that ALPI mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI‐based treatments in intestinal inflammatory disorders.
Keywords	inflammatory bowel diseases ; intestinal phosphatase alkaline ; monogenic disease ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
Subject code	610
Language	English
Publishing date	2018-04-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Author Correction

Eva Gonçalves Serra / Tobias Schwerd / Loukas Moutsianas / Athena Cavounidis / Laura Fachal / Sumeet Pandey / Jochen Kammermeier / Nicholas M. Croft / Carsten Posovszky / Astor Rodrigues / Richard K. Russell / Farah Barakat / Marcus K. H. Auth / Robert Heuschkel / Matthias Zilbauer / Krzysztof Fyderek / Christian Braegger / Simon P. Travis / Jack Satsangi /

Miles Parkes / Nikhil Thapar / Helen Ferry / Julie C. Matte / Kimberly C. Gilmour / Andrzej Wedrychowicz / Peter Sullivan / Carmel Moore / Jennifer Sambrook / Willem Ouwehand / David Roberts / John Danesh / Toni A. Baeumler / Tudor A. Fulga / Eli M Carrami / Ahmed Ahmed / Rachel Wilson / Jeffrey C. Barrett / Abdul Elkadri / Anne M. Griffiths / COLORS in IBD group investigators / Oxford IBD cohort study investigators / INTERVAL Study / Swiss IBD cohort investigators / UK IBD Genetics Consortium / NIDDK IBD Genetics Consortium / Scott B. Snapper / Neil Shah / Aleixo M. Muise / David C. Wilson / Holm H. Uhlig

Nature Communications, Vol 13, Iss 1, Pp 1-

Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

2022 Volume 1

Keywords	Science ; Q
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Rac2-deficiency leads to exacerbated and protracted colitis in response to Citrobacter rodentium infection.

Ramzi Fattouh / Cong-Hui Guo / Grace Y Lam / Melanie G Gareau / Bo-Yee Ngan / Michael Glogauer / Aleixo M Muise / John H Brumell

PLoS ONE, Vol 8, Iss 4, p e

2013 Volume 61629

Abstract: Recent genetic-based studies have implicated a number of immune-related genes in the pathogenesis of inflammatory bowel disease (IBD). Our recent genetic studies showed that RAC2 is associated with human IBD; however, its role in disease pathogenesis is ... ...

Abstract	Recent genetic-based studies have implicated a number of immune-related genes in the pathogenesis of inflammatory bowel disease (IBD). Our recent genetic studies showed that RAC2 is associated with human IBD; however, its role in disease pathogenesis is unclear. Given Rac2's importance in various fundamental immune cell processes, we investigated whether a defect in Rac2 may impair host immune responses in the intestine and promote disease in the context of an infection-based (Citrobacter rodentium) model of colitis. In response to infection, Rac2(-/-) mice showed i) worsened clinical symptoms (days 13-18), ii) increased crypt hyperplasia at days 11 and 22 (a time when crypt hyperplasia was largely resolved in wild-type mice; WT), and iii) marked mononuclear cell infiltration characterized by higher numbers of T (CD3(+)) cells (day 22), compared to WT-infected mice. Moreover, splenocytes harvested from infected Rac2(-/-) mice and stimulated in vitro with C. rodentium lysate produced considerably higher levels of interferon-γ and interleukin-17A. The augmented responses observed in Rac2(-/-) mice did not appear to stem from Rac2's role in NADPH oxidase-driven reactive oxygen species production as no differences in crypt hyperplasia, nor inflammation, were observed in infected NOX2(-/-) mice compared to WT. Collectively, our findings demonstrate that Rac2(-/-) mice develop more severe disease when subjected to a C. rodentium-induced model of infectious colitis, and suggest that impaired Rac2 function may promote the development of IBD in humans.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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