USP28 potentiates endothelial necroptosis via deubiquitinating NMMHC IIA in septic male mice
Abstract
Endothelial dysfunction contributes to multi-organ injury in sepsis, but the underlying mechanisms remain incompletely understood. Here we show that endothelial ubiquitin-specific protease 28 (USP28) is increased in patients with sepsis and in male mice in a murine polymicrobial sepsis model. Mechanistically, USP28 stabilizes non-muscle myosin heavy chain IIA (NMMHC IIA) by removing K48-linked ubiquitination at K1413. Moreover, NMMHC IIA promotes interferon-α/β receptor 1 (IFNAR1) trafficking to the plasma membrane, enhancing IFNAR1/signal transducer and activator of transcription 1 (STAT1) signaling and endothelial necroptosis. In turn, STAT1 transcriptionally increases USP28 expression, forming a positive feedback loop. Endothelial USP28 deletion or pharmacological inhibition attenuates sepsis-induced multi-organ injury, whereas USP28 overexpression exacerbates it. Conversely, endothelial NMMHC IIA or IFNAR1 overexpression largely abrogates the protection conferred by USP28 deficiency in septic male mice. These findings identify a USP28–NMMHC IIA axis that promotes endothelial necroptosis and multi-organ injury in sepsis through IFNAR1/STAT1 signaling.
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BibTeX
@article{tang2026usp28,
title = {{USP28 potentiates endothelial necroptosis via deubiquitinating NMMHC IIA in septic male mice}},
author = {Jiahui Tang and Dingji Hu and Mengchen Xu and Haiyu Chen and Shuaishuai Gong and Fang Li and Boyang Yu and Yuanyuan Zhang and Songqiao Liu and Junping Kou},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78666-8},
url = {https://www.nature.com/articles/s41467-026-78666-8},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - USP28 potentiates endothelial necroptosis via deubiquitinating NMMHC IIA in septic male mice
AU - Jiahui Tang
AU - Dingji Hu
AU - Mengchen Xu
AU - Haiyu Chen
AU - Shuaishuai Gong
AU - Fang Li
AU - Boyang Yu
AU - Yuanyuan Zhang
AU - Songqiao Liu
AU - Junping Kou
PY - 2026
DA - 2026/10/15
JO - Nature Communications
DO - 10.1038/s41467-026-78666-8
UR - https://www.nature.com/articles/s41467-026-78666-8
AB - Endothelial dysfunction contributes to multi-organ injury in sepsis, but the underlying mechanisms remain incompletely understood. Here we show that endothelial ubiquitin-specific protease 28 (USP28) is increased in patients with sepsis and in male mice in a murine polymicrobial sepsis model. Mechanistically, USP28 stabilizes non-muscle myosin heavy chain IIA (NMMHC IIA) by removing K48-linked ubiquitination at K1413. Moreover, NMMHC IIA promotes interferon-α/β receptor 1 (IFNAR1) trafficking to the plasma membrane, enhancing IFNAR1/signal transducer and activator of transcription 1 (STAT1) signaling and endothelial necroptosis. In turn, STAT1 transcriptionally increases USP28 expression, forming a positive feedback loop. Endothelial USP28 deletion or pharmacological inhibition attenuates sepsis-induced multi-organ injury, whereas USP28 overexpression exacerbates it. Conversely, endothelial NMMHC IIA or IFNAR1 overexpression largely abrogates the protection conferred by USP28 deficiency in septic male mice. These findings identify a USP28–NMMHC IIA axis that promotes endothelial necroptosis and multi-organ injury in sepsis through IFNAR1/STAT1 signaling.
SN - 2041-1723
ER -