Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy

Göös, Helka; Fogarty, Christopher L.; Sahu, Biswajyoti; Plagnol, Vincent; Rajamäki, Kristiina; Nurmi, Katariina; Liu, Xiaonan; Einarsdottir, Elisabet; Jouppila, Annukka; Pettersson, Tom; Vihinen, Helena; Krjutškov, Kaarel; Saavalainen, Päivi; Järvinen, Asko; Muurinen, Mari; Greco, Dario; Scala, Giovanni; Curtis, James; Nordström, Dan; Flaumenhaft, Robert; Vaarala, Outi; Kovanen, Panu E.; Keskitalo, Salla; Ranki, Annamari; Kere, Juha; Lehto, Markku; Notarangelo, Luigi D.; Nejentsev, Sergey; Eklund, Kari K.; Varjosalo, Markku; Taipale, Jussi; Seppänen, Mikko

doi:10.1016/j.jaci.2019.06.003

Cited by 41 publications

(24 citation statements)

References 39 publications

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“…In SGD, mutations in the gene CEBPE, which encodes the essential transcription factor CCAAT/enhancer binding protein e, have been identified, resulting in a complete lack of secondary and tertiary granules. 39,40 Apart from a defect in SG formation, neutrophils from SGD patients also have an abnormal bilobar nuclear morphology, [40][41][42] which clearly distinguishes SGD neutrophils from the normal nuclear morphology of GPS neutrophils. The SG deficiency in circulating neutrophils from patients with GPS is not as absolute as in SGD, which may contribute to the fact that patients with GPS do not suffer from recurrent or severe bacterial infections.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil specific granule and NETosis defects in gray platelet syndrome

et al. 2021

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Gray platelet syndrome (GPS) is an autosomal recessive bleeding disorder characterized by a lack of α-granules in platelets and progressive myelofibrosis. Rare loss-of-function variants in neurobeachin-like 2 (NBEAL2), a member of the family of beige and Chédiak-Higashi (BEACH) genes, are causal of GPS. It is suggested that BEACH domain containing proteins are involved in fusion, fission, and trafficking of vesicles and granules. Studies in knockout mice suggest that NBEAL2 may control the formation and retention of granules in neutrophils. We found that neutrophils obtained from the peripheral blood from 13 patients with GPS have a normal distribution of azurophilic granules but show a deficiency of specific granules (SGs), as confirmed by immunoelectron microscopy and mass spectrometry proteomics analyses. CD34+ hematopoietic stem cells (HSCs) from patients with GPS differentiated into mature neutrophils also lacked NBEAL2 expression but showed similar SG protein expression as control cells. This is indicative of normal granulopoiesis in GPS and identifies NBEAL2 as a potentially important regulator of granule release. Patient neutrophil functions, including production of reactive oxygen species, chemotaxis, and killing of bacteria and fungi, were intact. NETosis was absent in circulating GPS neutrophils. Lack of NETosis is suggested to be independent of NBEAL2 expression but associated with SG defects instead, as indicated by comparison with HSC-derived neutrophils. Since patients with GPS do not excessively suffer from infections, the consequence of the reduced SG content and lack of NETosis for innate immunity remains to be explored.

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Section: Discussionmentioning

confidence: 99%

Neutrophil specific granule and NETosis defects in gray platelet syndrome

et al. 2021

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“…Moreover, this is the first large-scale study to identify the dynamic PPIs of TFs using transient and proximal interactions catching BioID method. Finally, as defects in TF signalling often lead to severe pathological conditions [94][95][96] , and TFs function as downstream players of multiple signalling cascades 3 , identifying TF PPIs make a crucial contribution to pharmacological targeting of TF-related diseases.…”

Section: Discussionmentioning

confidence: 99%

Human transcription factor protein interaction networks

Göös

Kinnunen

Yadav

et al. 2021

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In participation of transcriptional regulation, transcription factors (TFs) interact with several other proteins. Here, we identified 7233 and 2176 protein-protein interactions for 110 different human TFs through proximity-dependent biotinylation (BioID) and affinity purification mass spectrometry (AP-MS), respectively. The BioID analysis resulted more high-confident interactions, highlighting the transient and dynamic nature of many of the TF interactions. Using clustering and correlation analyses, we identified subgroups of TFs associated with specific biological functions, such as RNA-splicing, actin signalling or chromatin remodeling. We also observed 203 TF-TF interactions, of which 175 were interactions with Nuclear Factor 1 (NFI) -family members, indicating uncharacterized cross-talk between NFI signalling and numerous other TF signalling. Moreover, TF interactions with basal transcription machinery were mainly observed through TFIID and SAGA complexes. This study, not only, provides a rich resource of human TF interactions, but also act as starting point directing future studies aimed at understanding TF mediated transcription.

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“…Patients with CAIN display recurrent fevers characterized by abdominal pain, lasting 4–5 days, and skin inflammatory manifestations, such as sterile abscesses, pyoderma gangrenosum and oral ulcerations. The mutant C/EBPϵ causes deregulated transcription of interleukins and interferon response genes in neutrophils ( 115 ).…”

Section: Introductionmentioning

confidence: 99%

Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation

et al. 2021

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A growing number of monogenic immune-mediated diseases have been related to genes involved in pathways of actin cytoskeleton remodeling. Increasing evidences associate cytoskeleton defects to autoinflammatory diseases and primary immunodeficiencies. We reviewed the pathways of actin cytoskeleton remodeling in order to identify inflammatory and immunological manifestations associated to pathological variants. We list more than twenty monogenic diseases, ranging from pure autoinflammatory conditions as familial Mediterranean fever, mevalonate kinase deficiency and PAPA syndrome, to classic and novel primary immunodeficiencies as Wiskott-Aldrich syndrome and DOCK8 deficiency, characterized by the presence of concomitant inflammatory and autoimmune manifestations, such as vasculitis and cytopenia, to severe and recurrent infections. We classify these disorders according to the role of the mutant gene in actin cytoskeleton remodeling, and in particular as disorders of transcription, elongation, branching and activation of actin. This expanding field of rare immune disorders offers a new perspective to all immunologists to better understand the physiological and pathological role of actin cytoskeleton in cells of innate and adaptive immunity.

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Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy

Cited by 41 publications

References 39 publications

Neutrophil specific granule and NETosis defects in gray platelet syndrome

Neutrophil specific granule and NETosis defects in gray platelet syndrome

Human transcription factor protein interaction networks

Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation

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