Reciprocal Regulation Between the SCF FBXO24 Ubiquitin E3 Ligase and FoxP1 Protein

Abigail Maloy; Sydney Walter; Arthur Mascilli; David C Klein; Santana M Lardo; James Londino; Toru Nyunoya; John McDyer; Mia Sun; Xuemei Zeng; Nathan Yates; Pamela Cantrell; Sarah J Hainer; Rama K Mallampalli; Divay Chandra

doi:10.1101/2025.05.23.653845

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Reciprocal Regulation Between the SCF FBXO24 Ubiquitin E3 Ligase and FoxP1 Protein

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Reciprocal Regulation Between the SCF FBXO24 Ubiquitin E3 Ligase and FoxP1 Protein

Abigail Maloy, Sydney Walter, Arthur Mascilli, David C Klein, Santana M Lardo, James Londino, Toru Nyunoya, John McDyer, Mia Sun, Xuemei Zeng, …

bioRxiv

Cold Spring Harbor Laboratory

05/28/2025

DOI: 10.1101/2025.05.23.653845

PMID: 40501863

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Preprint (Author's original) This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Forkhead Box Protein P1 (FoxP1) is a crucial transcriptional repressor essential for the development of the brain and heart. In adults, FoxP1 protein levels are dysregulated in a variety of disorders, including chronic obstructive pulmonary disease (COPD), atherosclerosis, and heart failure, where they causally contribute to disease pathogenesis. Although independent investigators have reported that FoxP1 protein is ubiquitinated, and E3 ligases have been identified for other FoxP family proteins, the identity of the E3 ligase that controls FoxP1 protein stability has remained unknown. Here, we identify FBXO24, a subunit of the Skp-Cullin-F-box (SCF) ubiquitin E3 ligase complex, as the regulator of FoxP1 ubiquitination and stability. Specifically, FBXO24 regulates K48 and K63 ubiquitination, complexes with, and co-localizes to the nucleus with FoxP1 protein in lung epithelial cells. Depleting FBXO24 reverses the unfolded protein response and cell death triggered by loss of FoxP1 protein in lung epithelium, suggesting a protective role. Additionally, FBXO24 knockout mice exhibit elevated FoxP1 levels in the lung and heart and reduced unfolded protein response activity after short-term cigarette smoke exposure. Intriguingly, we also uncovered bidirectional regulation, whereby FoxP1 protein binds to the FBXO24 promoter to suppress FBXO24 transcription. To our knowledge, this is the first evidence that a substrate for an E3 ligase can also regulate the E3 ligase and, therefore, control levels of other substrates, revealing new regulatory networks. Targeting FBXO24 may offer a therapeutic strategy for COPD, atherosclerosis, and heart failure by stabilizing FoxP1 levels in the heart and lungs and mitigating harmful downstream effects.

unfolded protein response

E3 ubiquitin ligase

FBXO24

lung epithelium

FoxP1

Details

Title: Subtitle: Reciprocal Regulation Between the SCF FBXO24 Ubiquitin E3 Ligase and FoxP1 Protein
Creators: Abigail Maloy - University of Pittsburgh
Sydney Walter - University of Pittsburgh
Arthur Mascilli - University of Pittsburgh
David C Klein - University of Pittsburgh
Santana M Lardo - University of Pittsburgh
James Londino - The Ohio State University
Toru Nyunoya - VA Pittsburgh Healthcare System
John McDyer - University of Pittsburgh
Mia Sun - University of Pittsburgh
Xuemei Zeng - University of Pittsburgh
Nathan Yates - University of Pittsburgh
Pamela Cantrell - University of Pittsburgh
Sarah J Hainer - UPMC Hillman Cancer Center
Rama K Mallampalli - The Ohio State University
Divay Chandra - University of Pittsburgh
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.1101/2025.05.23.653845
PMID: 40501863
ISSN: 2692-8205
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory; United States
Grant note: K23 HL126912 / NHLBI NIH HHS I01 BX006096 / BLRD VA R01 HL153400 / NHLBI NIH HHS R01 HL097376 / NHLBI NIH HHS S10 OD028483 / NIH HHS R01 HL096376 / NHLBI NIH HHS R35 GM133732 / NIGMS NIH HHS R01 HL149719 / NHLBI NIH HHS P30 CA047904 / NCI NIH HHS R01 HL081784 / NHLBI NIH HHS
Language: English
Date posted: 05/28/2025
Academic Unit: Internal Medicine
Record Identifier: 9985217040702771

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