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An ELF4 hypomorphic variant results in NK cell deficiency
Sandra Andrea Salinas, … , H. Daniel Lacorazza, Jordan S. Orange
Sandra Andrea Salinas, … , H. Daniel Lacorazza, Jordan S. Orange
Published December 8, 2022
Citation Information: JCI Insight. 2022;7(23):e155481. https://doi.org/10.1172/jci.insight.155481.
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Research Article Cell biology Immunology

An ELF4 hypomorphic variant results in NK cell deficiency

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Abstract

NK cell deficiencies (NKD) are a type of primary immune deficiency in which the major immunologic abnormality affects NK cell number, maturity, or function. Since NK cells contribute to immune defense against virally infected cells, patients with NKD experience higher susceptibility to chronic, recurrent, and fatal viral infections. An individual with recurrent viral infections and mild hypogammaglobulinemia was identified to have an X-linked damaging variant in the transcription factor gene ELF4. The variant does not decrease expression but disrupts ELF4 protein interactions and DNA binding, reducing transcriptional activation of target genes and selectively impairing ELF4 function. Corroborating previous murine models of ELF4 deficiency (Elf4–/–) and using a knockdown human NK cell line, we determined that ELF4 is necessary for normal NK cell development, terminal maturation, and function. Through characterization of the NK cells of the proband, expression of the proband’s variant in Elf4–/– mouse hematopoietic precursor cells, and a human in vitro NK cell maturation model, we established this ELF4 variant as a potentially novel cause of NKD.

Authors

Sandra Andrea Salinas, Emily M. Mace, Matilde I. Conte, Chun Shik Park, Yu Li, Joshua I. Rosario-Sepulveda, Sanjana Mahapatra, Emily K. Moore, Evelyn R. Hernandez, Ivan K. Chinn, Abigail E. Reed, Barclay J. Lee, Alexander Frumovitz, Richard A. Gibbs, Jennifer E. Posey, Lisa R. Forbes Satter, Akaluck Thatayatikom, Eric J. Allenspach, Theodore G. Wensel, James R. Lupski, H. Daniel Lacorazza, Jordan S. Orange

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Figure 7

ELF4 functional changes induced by p.T187N.

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ELF4 functional changes induced by p.T187N.
(A) I-TASSER prediction of E...
(A) I-TASSER prediction of ELF4 structure showing the backbone with a cluster predicted to form a binding pocket encircled and DNA binding residues with red arrow pointing at aa 187. (B) UCSF Chimera software analysis from predicted models of hydrogen bonds (green lines) with listed aa residue interactions of ELF4T187 (blue, left) and ELF4N187 (pink, right). (C) LIGPLOT software analysis from predicted models of Van der Waals interactions (pink) and hydrogen bonds, showing predicted interactions with aa within the same chain or proximal (across the black line) based on protein folding for ELF4T187 and ELF4N187. (D) Relative fluorescence units of luciferase promoter reporter (PRF1 and MDM2) for ELF4 T187N overexpression normalized to the WT control. (E) Independent repeats of ChIP quantitative PCR for overexpressed WT and T187N ELF4 bound to promoters (NT, nontransfected). (F) Salt-titrated extraction assay of chromatin-bound ELF4. Western blot run on a gel including the total cell lysate and the cytoplasmic and nuclear soluble fractions and a second gel including the chromatin-bound salt extraction. Showing the proteins detached with the increasing concentrations of salt from the chromatin-bound fraction after sequential extraction of the cytoplasmic, nuclear soluble, and chromatin-bound fractions (top, representative blot) with red lines indicating the significant difference in extraction between the WT and T187N ELF4 at lower salt concentrations. ELF4 expression normalized to loading control and subsequently to the wild-type control (bottom) across 3 independent experiments. The data represent mean ± SEM of ≥3 independent experiments. Western blot is representative of experiment repeated at least 3 times; *P < 0.05, **P < 0.01, ***P < 0.001, 2-tailed paired Student’s t test and Wilcoxon matched pairs signed-rank test.

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