PEAK1 maintains tight junctions in intestinal epithelial cells and resists colitis by inhibiting autophagy-mediated ZO-1 degradation

Zaikuan Zhang, Yajun Xie (), Qiying Yi, Jianing Liu, Lin Yang, Runzhi Wang, Jing Cai, Xinyi Li, Xiaosong Feng, Shixiang Yao, Zheng Pan, Magdalena Paolino () and Qin Zhou ()
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Zaikuan Zhang: Chongqing Medical University
Yajun Xie: Chongqing Medical University
Qiying Yi: Chongqing Medical University
Jianing Liu: Karolinska Institutet
Lin Yang: Chongqing Medical University
Runzhi Wang: Harbin Medical University
Jing Cai: Harbin Medical University
Xinyi Li: Chongqing Medical University
Xiaosong Feng: Chongqing Medical University
Shixiang Yao: Southwest University
Zheng Pan: Chongqing Medical University
Magdalena Paolino: Karolinska Institutet
Qin Zhou: Chongqing Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Tight junctions are crucial for maintaining intestinal barrier homeostasis, but how organisms modulate these junctions remain unclear. Here, we show a role for PEAK1 at cell-cell contact sites, where it interacts with ZO-1 via a conserved region spanning amino acids 714-731. This interaction masks the LC3-interacting region on ZO-1, preventing autophagy-mediated ZO-1 degradation and preserving the integrity of tight junctions in intestinal epithelial cells. Src-mediated phosphorylation of PEAK1 at Y724 promotes the binding between PEAK1 and ZO-1 to stabilize ZO-1 in intestinal epithelial cells. Additionally, PEAK1 binds to CSK to positively regulate Src activity. Loss of PEAK1 in intestinal epithelial cells leads to decreased Src activity and lower ZO-1 protein levels, resulting in disrupted tight junctions, both in vitro and in vivo. In mice, Peak1 deficiency increases intestinal epithelium permeability and exacerbates inflammation in experimentally induced colitis models. Our findings reveal PEAK1’s critical role in maintaining tight junction integrity and resistance to intestinal inflammation, extending its known function from promoting tumor cell proliferation and migration to essential physiological processes. These insights refine our understanding of the mechanisms regulating tight junctions and offer potential therapeutic targets for enhancing epithelial barrier function and treating related diseases.

Date: 2025
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DOI: 10.1038/s41467-025-62107-z

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