Live Cell Imaging Demonstrates Multiple Routes Toward a STAT1 Gain-of-Function Phenotype

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2020 Jun 26

PMID 32582194

Citations 8

Authors

Simone Giovannozzi

Veerle Lemmens

Jelle Hendrix

Rik Gijsbers

Rik Schrijvers

Affiliations

Soon will be listed here.

Abstract

Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations result in a primary immunodeficiency (PID) characterized typically by chronic mucocutaneous candidiasis (CMC), but a wider phenotypic range is reported and remains unexplained from a pathophysiological point-of-view. We hypothesized that different STAT1 GOF mutations may result in distinct molecular mechanisms, possibly explaining the variable phenotypes observed in patients. We selected STAT1 GOF mutants (R274W, R321S, T419R, and N574I) that are spread over the protein and studied their dynamic behavior in U3A and HeLa cell lines. All GOF mutants showed increased STAT1 phosphorylation compared to STAT1 WT. Real-time imaging demonstrated three underlying mechanisms for STAT1 GOF: (i) R274W showed a faster nuclear accumulation, (ii) both R321S and N574I showed a reduced nuclear mobility and slower dephosphorylation, whereas (iii) T419R was near-immobile in the nucleus, potentially due to enhanced binding to chromatin.

Citing Articles

Leveraging Systems Immunology to Optimize Diagnosis and Treatment of Inborn Errors of Immunity.

Mauracher A, Henrickson S Front Syst Biol. 2023; 2.

PMID: 37670772 PMC: 10477056. DOI: 10.3389/fsysb.2022.910243.

JAKs and STATs from a Clinical Perspective: Loss-of-Function Mutations, Gain-of-Function Mutations, and Their Multidimensional Consequences.

Ott N, Faletti L, Heeg M, Andreani V, Grimbacher B J Clin Immunol. 2023; 43(6):1326-1359.

PMID: 37140667 PMC: 10354173. DOI: 10.1007/s10875-023-01483-x.

Case report: Myocarditis in congenital STAT1 gain-of function.

Staels F, Roosens W, Giovannozzi S, Moens L, Bogaert J, Iglesias-Herrero C Front Immunol. 2023; 14:1095595.

PMID: 37020552 PMC: 10067556. DOI: 10.3389/fimmu.2023.1095595.

Systems Immunology Analyses of Gain-of-Function Immune Phenotypes Reveal Heterogeneous Response to IL-6 and Broad Immunometabolic Roles for STAT1.

Kaviany S, Bartkowiak T, Dulek D, Khan Y, Hayes M, Schaefer S Immunohorizons. 2022; 6(7):447-464.

PMID: 35840326 PMC: 9623573. DOI: 10.4049/immunohorizons.2200041.

JAK inhibition in a patient with a STAT1 gain-of-function variant reveals STAT1 dysregulation as a common feature of aplastic anemia.

Rosenberg J, Peters J, Hughes T, Lareau C, Ludwig L, Massoth L Med. 2022; 3(1):42-57.e5.

PMID: 35590143 PMC: 9123284. DOI: 10.1016/j.medj.2021.12.003.

References

Digman M, Sengupta P, Wiseman P, Brown C, Horwitz A, Gratton E . Fluctuation correlation spectroscopy with a laser-scanning microscope: exploiting the hidden time structure. Biophys J. 2005; 88(5):L33-6. PMC: 1305524. DOI: 10.1529/biophysj.105.061788. View

Kobbe R, Kolster M, Fuchs S, Schulze-Sturm U, Jenderny J, Kochhan L . Common variable immunodeficiency, impaired neurological development and reduced numbers of T regulatory cells in a 10-year-old boy with a STAT1 gain-of-function mutation. Gene. 2016; 586(2):234-8. DOI: 10.1016/j.gene.2016.04.006. View

Wenta N, Strauss H, Meyer S, Vinkemeier U . Tyrosine phosphorylation regulates the partitioning of STAT1 between different dimer conformations. Proc Natl Acad Sci U S A. 2008; 105(27):9238-43. PMC: 2453697. DOI: 10.1073/pnas.0802130105. View

Liu L, Okada S, Kong X, Kreins A, Cypowyj S, Abhyankar A . Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med. 2011; 208(8):1635-48. PMC: 3149226. DOI: 10.1084/jem.20110958. View

Aldave J, Cachay E, Nunez L, Chunga A, Murillo S, Cypowyj S . A 1-year-old girl with a gain-of-function STAT1 mutation treated with hematopoietic stem cell transplantation. J Clin Immunol. 2013; 33(8):1273-5. DOI: 10.1007/s10875-013-9947-5. View

Maeshima K, Ishii K, Shibata H . An Adult Fatal Case with a Gain-of-function Mutation Associated with Multiple Autoimmune Diseases. J Rheumatol. 2018; 46(3):325-327. DOI: 10.3899/jrheum.180210. View

Zimmerman O, Rosler B, Zerbe C, Rosen L, Hsu A, Uzel G . Risks of Ruxolitinib in Gain-of-Function-Associated Severe Fungal Disease. Open Forum Infect Dis. 2017; 4(4):ofx202. PMC: 5714179. DOI: 10.1093/ofid/ofx202. View

Kilic S, Puel A, Casanova J . Orf Infection in a Patient with Stat1 Gain-of-Function. J Clin Immunol. 2014; 35(1):80-3. DOI: 10.1007/s10875-014-0111-7. View

Boisson-Dupuis S, Kong X, Okada S, Cypowyj S, Puel A, Abel L . Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr Opin Immunol. 2012; 24(4):364-78. PMC: 3477860. DOI: 10.1016/j.coi.2012.04.011. View

10.

Fujiki R, Hijikata A, Shirai T, Okada S, Kobayashi M, Ohara O . Molecular mechanism and structural basis of gain-of-function of STAT1 caused by pathogenic R274Q mutation. J Biol Chem. 2017; 292(15):6240-6254. PMC: 5391754. DOI: 10.1074/jbc.M116.753848. View

11.

Petersen J, Staab J, Bader O, Buhl T, Ivetic A, Meyer T . Identification of a distinct subset of disease-associated gain-of-function missense mutations in the STAT1 coiled-coil domain as system mutants. Mol Immunol. 2019; 114:30-40. DOI: 10.1016/j.molimm.2019.07.008. View

12.

Hendrix J, Dekens T, Schrimpf W, Lamb D . Arbitrary-Region Raster Image Correlation Spectroscopy. Biophys J. 2016; 111(8):1785-1796. PMC: 5073057. DOI: 10.1016/j.bpj.2016.09.012. View

13.

Vargas-Hernandez A, Mace E, Zimmerman O, Zerbe C, Freeman A, Rosenzweig S . Ruxolitinib partially reverses functional natural killer cell deficiency in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations. J Allergy Clin Immunol. 2017; 141(6):2142-2155.e5. PMC: 5924437. DOI: 10.1016/j.jaci.2017.08.040. View

14.

Mikuni S, Yamamoto J, Horio T, Kinjo M . Negative Correlation between the Diffusion Coefficient and Transcriptional Activity of the Glucocorticoid Receptor. Int J Mol Sci. 2017; 18(9). PMC: 5618504. DOI: 10.3390/ijms18091855. View

15.

Yuasa K, Hijikata T . Distal regulatory element of the STAT1 gene potentially mediates positive feedback control of STAT1 expression. Genes Cells. 2015; 21(1):25-40. DOI: 10.1111/gtc.12316. View

16.

Baris S, Alroqi F, Kiykim A, Karakoc-Aydiner E, Ogulur I, Ozen A . Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1. J Clin Immunol. 2016; 36(7):641-8. PMC: 5556363. DOI: 10.1007/s10875-016-0312-3. View

17.

Kraus T, Lau J, Parisien J, Horvath C . A hybrid IRF9-STAT2 protein recapitulates interferon-stimulated gene expression and antiviral response. J Biol Chem. 2003; 278(15):13033-8. DOI: 10.1074/jbc.M212972200. View

18.

van de Veerdonk F, Koenen H, van der Velden W, van der Meer J, Netea M . Immunotherapy with G-CSF in patients with chronic mucocutaneous candidiasis. Immunol Lett. 2015; 167(1):54-6. DOI: 10.1016/j.imlet.2015.05.008. View

19.

Hirahara K, Onodera A, Villarino A, Bonelli M, Sciume G, Laurence A . Asymmetric Action of STAT Transcription Factors Drives Transcriptional Outputs and Cytokine Specificity. Immunity. 2015; 42(5):877-89. PMC: 11037422. DOI: 10.1016/j.immuni.2015.04.014. View

20.

Forbes L, Vogel T, Cooper M, Castro-Wagner J, Schussler E, Weinacht K . Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations. J Allergy Clin Immunol. 2018; 142(5):1665-1669. PMC: 6322659. DOI: 10.1016/j.jaci.2018.07.020. View