2. Academic Validation
  3. PEAK1 maintains tight junctions in intestinal epithelial cells and resists colitis by inhibiting autophagy-mediated ZO-1 degradation

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

  • Nat Commun. 2025 Jul 24;16(1):6777. doi: 10.1038/s41467-025-62107-z.
Zaikuan Zhang # 1 2,  Yajun Xie # 3 4,  Qiying Yi # 5,  Jianing Liu # 6 7,  Lin Yang 1,  Runzhi Wang 8,  Jing Cai 8,  Xinyi Li 1,  Xiaosong Feng 1,  Shixiang Yao 9,  Zheng Pan 10,  Magdalena Paolino 11 12,  Qin Zhou 13 14
Affiliations

Affiliations

  • 1 The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing, P. R. China.
  • 2 Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, P. R. China.
  • 3 The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing, P. R. China. yjxie@cqmu.edu.cn.
  • 4 Western Institute of Digital-Intelligent Medicine, Chongqing, P. R. China. yjxie@cqmu.edu.cn.
  • 5 The Experimental Animal Center, Chongqing Medical University, Chongqing, P. R. China.
  • 6 Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
  • 7 Karolinska University Hospital, Stockholm, Sweden.
  • 8 The School of Basic Medical Sciences, Harbin Medical University, Harbin, P. R. China.
  • 9 The College of Food Science, Southwest University, Chongqing, P. R. China.
  • 10 The College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, P. R. China.
  • 11 Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. magdalena.paolino@ki.se.
  • 12 Karolinska University Hospital, Stockholm, Sweden. magdalena.paolino@ki.se.
  • 13 The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing, P. R. China. zhouqin@hrbmu.edu.cn.
  • 14 The School of Basic Medical Sciences, Harbin Medical University, Harbin, P. R. China. zhouqin@hrbmu.edu.cn.
  • # Contributed equally.
PMID: 40707483 DOI: 10.1038/s41467-025-62107-z
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.

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