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AMBRA1 promotes intestinal inflammation by antagonizing PP4R1/PP4c mediated IKK dephosphorylation in an autophagy-independent manner

Cell Death & Differentiation (2024)Cite this article

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Abstract

IκB kinase (IKK) complex is central regulators of the NF-κB pathway, and dysregulation of IKK phosphorylation leads to hyperactivation of proinflammatory response in various chronic inflammatory diseases, including inflammatory bowel disease (IBD). However, the dynamic modulation of IKK phosphorylation and dephosphorylation in intestinal inflammation remains uncharacterized. Here, we found that autophagy/beclin-1 regulator 1 (AMBRA1) was highly expressed in inflamed colons in a colitis mouse model and in clinical IBD samples. Importantly, AMBRA1 deletion significantly decreased proinflammatory cytokine expression and enhanced the therapeutic effect of infliximab on intestinal inflammation. Mechanistically, the N-term F1 domain of AMBRA1 was required for AMBRA1 to competitively interact with protein phosphatase 4 regulatory subunit 1 (PP4R1) and catalytic protein phosphatase 4 (PP4c) to suppress their interactions with IKK, promote the dissociation of the PP4R1/PP4c complex, and antagonize the dephosphorylation activity of this complex towards the IKK complex. In response to TNF-α stimulation, IKKα phosphorylates AMBRA1 at S1043 to stabilize AMBRA1 expression by impairing its binding to Cullin4A (CUL4A) to decrease its CUL4A-mediated K48-linked ubiquitination. Overall, our study identifies an autophagy-independent function of AMBRA1 as a positive modulator of IKK phosphorylation to promote intestinal inflammation, thus providing a new targeted therapeutic strategy for patients with refractory IBD.

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Fig. 1: AMBRA1 expression is increased in the inflamed colon tissues from IBD patients.
Fig. 2: AMBRA1 knockdown alleviates DSS-induced intestinal mucosal inflammation in mice.
Fig. 3: AMBRA1 interacts with the IKK complex to promote NF-κB activation.
Fig. 4: The N-terminal domain is required for AMBRA1 to antagonize dephosphorylation of the IKK complex mediated by PP4R1/PP4c.
Fig. 5: The IKKα kinase phosphorylates AMBRA1 at S1043 to stabilize the AMBRA1 protein by inhibiting its binding to CUL4A.
Fig. 6: AMBRA1 diminishes the therapeutic effect of IFX on intestinal inflammation in vitro.
Fig. 7: Knockout of AMBRA1 enhances the therapeutic effect of IFX on DSS-induced acute colitis in vivo.
Fig. 8: Schematic diagram of the findings in this study.

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Data availability

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 82270549, 82000481, 82372648, 82000494) and Natural Science Foundation of Shanghai (No. 22ZR1440500).

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  1. These authors contributed equally: Weimin Xu, Zhebin Hua, Yaosheng Wang.

Authors and Affiliations

  1. Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 200092, China

    Weimin Xu, Zhebin Hua, Yaosheng Wang, Wenbo Tang, Weijun Ou, Fangyuan Liu, Yiqing Yang, Wenjun Ding, Zhongchuan Wang, Long Cui, Chen-Ying Liu & Peng Du

  2. Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China

    Weimin Xu, Zhebin Hua, Yaosheng Wang, Wenbo Tang, Weijun Ou, Fangyuan Liu, Yiqing Yang, Wenjun Ding, Zhongchuan Wang, Long Cui, Chen-Ying Liu & Peng Du

  3. Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 200092, China

    Wensong Ge & YingWei Chen

  4. Department of Gastroenterology, Rui Jin Hospital, affiliate to Shanghai Jiao Tong University, school of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China

    Yubei Gu

  5. Department of Gastroenterology, The Shanghai Tenth People’s Hospital, Tongji University, Shanghai, 200072, China

    Xiaolei Wang

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  1. Weimin Xu
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Contributions

Peng Du, Chen-Ying Liu and YingWei Chen designed the research. Weimin Xu, Zhebin Hua and Yaosheng Wang performed experiments and/or analyzed data. Weimin Xu and Chen-Ying Liu wrote the manuscript. Wenbo Tang, Weijun Ou, Fangyuan Liu, Yiqing Yang, Wenjun Ding and Wensong Ge assisted some analysis and collected the specimens from patients. Zhongchuan Wang, Long Cui, Yubei Gu and Xiaolei Wang reviewed and revised the manuscript. All authors approved the final version.

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Correspondence to YingWei Chen, Chen-Ying Liu or Peng Du.

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The study was approved by the Ethics Committee of Xinhua Hospital (No. XHEC-NSFC-2022-113). All mouse studies were approved, and all animals were manipulated according to the protocols approved by the Animal Care and Use Committees of Xinhua Hospital and animal care was conducted in accordance with institutional guidelines.

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Xu, W., Hua, Z., Wang, Y. et al. AMBRA1 promotes intestinal inflammation by antagonizing PP4R1/PP4c mediated IKK dephosphorylation in an autophagy-independent manner. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01275-9

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