Interleukin enhancer binding factor 2 (Ilf2) and kidney epithelial stress resilience

Cao, Shuang; López-Cayuqueo, Karen I.; Leiz, Janna; Boivin, Felix J.; Markó, Lajos; Hinze, Christian; Schmitz, Jessica; Bräsen, Jan Hinrich; Schmidt-Ott, Kai

Interleukin enhancer binding factor 2 (Ilf2) and kidney epithelial stress resilience

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Item Type:	Preprint
Title:	Interleukin enhancer binding factor 2 (Ilf2) and kidney epithelial stress resilience
Creators Name:	Cao, Shuang, López-Cayuqueo, Karen I., Leiz, Janna, Boivin, Felix J., Markó, Lajos, Hinze, Christian, Schmitz, Jessica, Bräsen, Jan Hinrich and Schmidt-Ott, Kai
Abstract:	BACKGROUND: Epithelial cells in the renal medulla are continuously exposed to hyperosmolality, hypoxia, and oxidative stress, yet they display remarkable resilience. The transcriptional programs that endow this intrinsic stress tolerance remain incompletely defined. METHODS: We integrated single-nucleus RNA sequencing of mouse kidneys, computational transcription factor (TF) prioritization, and single-cell CRISPR interference screening (Perturb-seq) in inner medullary collecting duct (IMCD3) cells to systematically identify TFs mediating epithelial stress adaptation. The role of Ilf2 (Interleukin Enhancer Binding Factor 2) was further evaluated in IMCD3 cells by bulk RNA-seq, splicing analysis, functional assays under hyperosmotic stress, as well as in a mouse model of kidney ischemia–reperfusion injury (IRI) and kidney tissues from patients with early and advanced chronic kidney disease (CKD). RESULTS: Computational prediction and Perturb-seq identified known and novel TFs, that regulate gene expression programs in kidney medullary tubules. Among them, Ilf2 (also called NF45) emerged as a previously unrecognized regulator: Ilf2 knockdown in IMCD3 cells disrupted transcriptional and splicing programs linked to cell proliferation, cytoskeletal organization, and stress adaptation. Ilf2-deficient cells exhibited reduced proliferation, impaired nuclear integrity, and increased sensitivity to hyperosmotic stress. In mouse kidneys, Ilf2 expression increased during tubular repair after IRI, accompanied by induction of Ilf2-dependent transcripts and splicing events. Human kidneys with advanced CKD displayed elevated expression and cytoplasmic translocation of ILF2, suggesting a conserved stress-adaptive response. CONCLUSIONS: ILF2 orchestrates both transcriptional and post-transcriptional regulatory mechanisms to sustain kidney epithelial stress resilience. Our findings highlight ILF2 as a potential tubular stress biomarker and therapeutic target for enhancing renoprotection.
Keywords:	Animals, Mice
Source:	bioRxiv
Publisher:	Cold Spring Harbor Laboratory Press
Article Number:	2025.08.12.667599v3
Date:	21 November 2025
Additional Information:	External datasets in Gene Expression Omnibus (GEO) are currently private and scheduled to be released on Jun 30, 2027. Reviewer tokens are the following: GSE299239 (reviewer token onwzwycqtvmntgl), GSE299244 (reviewer token gxibwcquhngpnml), GSE299248 (reviewer token qtklsmwqffwppsz), GSE299251 (reviewer token GSE299251), and GSE299249 (reviewer token edutiqmqxhqxnqp).
Official Publication:	https://doi.org/10.1101/2025.08.12.667599
Related to:	URL URL Type https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE299239 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE299244 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE299248 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE299251 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE299249 External Dataset https://doi.org/10.26068/mhhrpm/20250530-000 External Dataset https://github.com/shuangcao-mhh/Perturb-seq-screening-in-IMCD3-cells Software

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