IRF2BP2 Mutation Is Associated with Increased STAT1 and STAT5 Activation in Two Family Members with Inflammatory Conditions and Lymphopenia

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Palmroth , M , Viskari , H , Seppänen , M R J , Keskitalo , S , Virtanen , A , Varjosalo , M , Silvennoinen , O & Isomäki , P 2021 , ' IRF2BP2 Mutation Is Associated with Increased STAT1 and STAT5 Activation in Two Family Members with Inflammatory Conditions and Lymphopenia ' , Pharmaceuticals , vol. 14 , no. 8 , 797 . https://doi.org/10.3390/ph14080797

Title: IRF2BP2 Mutation Is Associated with Increased STAT1 and STAT5 Activation in Two Family Members with Inflammatory Conditions and Lymphopenia
Author: Palmroth, Maaria; Viskari, Hanna; Seppänen, Mikko R. J.; Keskitalo, Salla; Virtanen, Anniina; Varjosalo, Markku; Silvennoinen, Olli; Isomäki, Pia
Contributor organization: Children's Hospital
HUS Children and Adolescents
Clinicum
Department of Medicine
Institute of Biotechnology
Molecular Systems Biology
Biosciences
Helsinki Institute of Life Science HiLIFE
Date: 2021-08
Language: eng
Number of pages: 14
Belongs to series: Pharmaceuticals
ISSN: 1424-8247
DOI: https://doi.org/10.3390/ph14080797
URI: http://hdl.handle.net/10138/335089
Abstract: Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional coregulator that has an important role in the regulation of the immune response. IRF2BP2 has been associated with the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway, but its exact role remains elusive. Here, we identified a novel clinical variant, IRF2BP2 c.625_665del, from two members of a family with inflammatory conditions and investigated the function of IRF2BP2 and c.625_665del mutation in JAK-STAT pathway activation and inflammatory signaling. The levels of constitutive and cytokine-induced phosphorylation of STATs and total STAT1 in peripheral blood monocytes, T cells, and B cells from the patients and four healthy controls were measured by flow cytometry. Inflammation-related gene expression was studied in peripheral blood mononuclear cells using direct digital detection of mRNA (NanoString). Finally, we studied the relationship between IRF2BP2 and STAT1 activation using a luciferase reporter system in a cell model. Our results show that patients having the IRF2BP2 c.625_665del mutation presented overexpression of STAT1 protein and increased constitutive activation of STAT1. In addition, interferon-induced JAK-STAT signaling was upregulated, and several interferon-inducible genes were overexpressed. Constitutive phosphorylation of STAT5 was also found to be upregulated in CD4(+) T cells from the patients. Using a cell model, we show that IRF2BP2 was needed to attenuate STAT1 transcriptional activity and that IRF2BP2 c.625_665del mutation failed in this. We conclude that IRF2BP2 has an important role in suppressing immune responses elicited by STAT1 and STAT5 and suggest that aberrations in IRF2BP2 can lead to abnormal function of intrinsic immunity.
Subject: interferon regulatory factor-2 binding protein-2 (IRF2BP2)
JAK-STAT pathway
interferons
inflammation
SELECTIVELY MODULATES APOPTOSIS
ACUTE PROMYELOCYTIC LEUKEMIA
FINGER PROTEINS
IDENTIFICATION
TRANSCRIPTION
FUSION
GENE
PATHWAY
DISEASE
COMPLEX
1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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